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Williams AC, Content VG, Alexander LM. Salsalate negatively impacts microvascular function in women with endometriosis. Am J Physiol Heart Circ Physiol 2025; 328:H915-H922. [PMID: 40047802 DOI: 10.1152/ajpheart.00012.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/05/2025] [Accepted: 03/03/2025] [Indexed: 03/29/2025]
Abstract
Women with endometriosis, an inflammatory disease, are at increased risk of cardiovascular disease and demonstrate impaired microvascular endothelial function, characterized by reduced nitric oxide (NO)-mediated vasodilation. In some clinical cohorts, nuclear factor-kappa B (NFκB) inhibition with salsalate improves endothelial function. We hypothesized that salsalate would improve cutaneous microvascular endothelial function in women with endometriosis. Following placebo or salsalate (3,000 mg·day-1 for 5 days), four intradermal microdialysis probes were placed in 11 women (33 ± 7 yr) with endometriosis. Local heating units (set to 33°C) and laser-Doppler flowmetry (red blood cell flux) probes were placed over the probes. Increasing doses of acetylcholine (ACh; dissolved in lactated Ringer's solution) were perfused, alone (control) or coperfused with: NG-nitro-l-arginine methyl ester (l-NAME), atorvastatin (statin), or l-NAME + statin (combo). Maximal vasodilation was then induced (local heat at 43°C + sodium nitroprusside perfusion). Data were normalized as percentage of maximal cutaneous vascular conductance (CVC%max red blood cell flux/mean arterial pressure). To measure macrovascular endothelial function, flow-mediated dilation (FMD) was additionally performed. During placebo, coperfusion with statin did not impact the CVC%max ACh dose-response (P = 0.93). Oral salsalate attenuated the CVC%max response to ACh perfusion alone (P < 0.01) but did not impact the l-NAME site (P = 0.09). Salsalate significantly augmented the CVC%max response of the statin site (P < 0.01) but did not affect the combo site response (P = 1.00). FMD was not different between treatments (P = 0.79). Salsalate treatment impairs vasodilation in the cutaneous microcirculation in women with endometriosis through non-NO-dependent mechanisms.NEW & NOTEWORTHY Our results show that oral salsalate treatment negatively impacts microvascular function but does not alter macrovascular function. In contrast to the majority of other clinical populations with endothelial dysfunction, salsalate treatment reduces microcirculatory function through non-NO-dependent mechanisms in women with endometriosis.
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Affiliation(s)
- Auni C Williams
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
| | - Virginia G Content
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
| | - Lacy M Alexander
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
- Center for Healthy Aging, The Pennsylvania State University, University Park, Pennsylvania, United States
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Baik S, Hong S, Kim HJ, Jeong HS, Lee H, Lee J. Relative protective activities of avenanthramide A, B, and C against H2O2-induced endothelial dysfunction in EA.hy926 cells. Biosci Biotechnol Biochem 2025; 89:268-274. [PMID: 39558575 DOI: 10.1093/bbb/zbae170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 11/05/2024] [Indexed: 11/20/2024]
Abstract
This study compared the antihypertensive effects of avenanthramides A, B, and C, with a focus on their antioxidant and anti-inflammatory properties. Treatment with avenanthramides A, B, and C (50 μm) significantly enhanced cell viability and nitric oxide production in H2O2-induced endothelial dysfunction in EA.hy926 cells. Avenanthramides notably increased the levels of antioxidant enzymes and glutathione while reducing malondialdehyde and reactive oxygen species. Moreover, avenanthramides promoted the Nrf2 translocation to nucleus, enhancing the expression of antioxidant enzymes. Furthermore, avenanthramides inhibited the protein levels of iNOS and COX-2, as well as the phosphorylation of IkBα and translocation of p65, thereby mitigating endothelial inflammation. Molecular docking analysis revealed that avenanthramide A exhibited the strongest binding affinity for HO-1 and iNOS, which was correlated with its superior biological activity. Overall, by upregulating Nrf2/HO-1 pathways and downregulating NF-kB pathways, avenanthramides show potential as therapeutic agents for the treatment of endothelial dysfunction.
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Affiliation(s)
- Seungjoo Baik
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Seonghwa Hong
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Hyun Joo Kim
- Department of Central Area Crop Science, National Institute of Crop Science, Rural Development Administration, Suwon, Gyeonggi, Korea
| | - Heon Sang Jeong
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Hana Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Junsoo Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, Korea
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Content VG, Williams AC, Alexander LM. Inhibition of nuclear factor-κB activation improves non-nitric oxide-mediated cutaneous microvascular function in reproductive-aged healthy women. Am J Physiol Heart Circ Physiol 2024; 327:H364-H369. [PMID: 38847757 PMCID: PMC11444226 DOI: 10.1152/ajpheart.00204.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/28/2024] [Accepted: 06/05/2024] [Indexed: 07/17/2024]
Abstract
The transcriptional regulator nuclear factor-κB (NF-κB) is a mediator of endothelial dysfunction. Inhibiting NF-κB with salsalate is used to investigate inflammatory mechanisms contributing to accelerated cardiovascular disease risk. However, in the absence of disease, inhibition of NF-κB can impact redox mechanisms, resulting in paradoxically decreased endothelial function. This study aimed to measure microvascular endothelial function during inhibition of the transcriptional regulator NF-κB in reproductive-aged healthy women. In a randomized, single-blind, crossover, placebo-controlled design, nine healthy women were randomly assigned oral salsalate (1,500 mg, twice daily) or placebo treatments for 5 days. Subjects underwent graded perfusion with the endothelium-dependent agonist acetylcholine (ACh, 10-10 to 10-1 M, 33°C) alone and in combination with 15 mM NG-nitro-l-arginine methyl ester [l-NAME; nonselective nitric oxide (NO) synthase inhibitor] through intradermal microdialysis. Laser-Doppler flux was measured over each microdialysis site, and cutaneous vascular conductance (CVC) was calculated as flux divided by mean arterial pressure and normalized to site-specific maximum (CVC%max; 28 mM sodium nitroprusside + 43°C). The l-NAME sensitive component was calculated as the difference between the areas under the dose-response curves. During the placebo and salsalate treatments, the l-NAME sites were reduced compared with the control sites (both P < 0.0001). Across treatments, there was a significant difference between the control and l-NAME sites, where both sites shifted upward following salsalate treatment (both P < 0.0001), whereas the l-NAME-sensitive component was not different (P = 0.94). These data demonstrate that inhibition of the transcriptional regulator NF-κB improves cutaneous microvascular function in reproductive-aged healthy women through non-NO-dependent mechanisms.NEW & NOTEWORTHY The transcription factor nuclear factor-κB (NF-κB) regulates multiple aspects of innate and adaptive immunity by encoding for genes that participate in inflammation and impact endothelial function following NF-κB inhibition with salsalate treatment. Our results show that cutaneous microvascular function is increased through non-nitric oxide (NO)-dependent mechanisms following salsalate treatment in reproductive-aged healthy women.
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Affiliation(s)
- Virginia G Content
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
| | - Auni C Williams
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
| | - Lacy M Alexander
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, United States
- Center for Healthy Aging, The Pennsylvania State University, University Park, Pennsylvania, United States
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4
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Wahl D, Clayton ZS. Peripheral vascular dysfunction and the aging brain. Aging (Albany NY) 2024; 16:9280-9302. [PMID: 38805248 PMCID: PMC11164523 DOI: 10.18632/aging.205877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 03/28/2024] [Indexed: 05/29/2024]
Abstract
Aging is the greatest non-modifiable risk factor for most diseases, including cardiovascular diseases (CVD), which remain the leading cause of mortality worldwide. Robust evidence indicates that CVD are a strong determinant for reduced brain health and all-cause dementia with advancing age. CVD are also closely linked with peripheral and cerebral vascular dysfunction, common contributors to the development and progression of all types of dementia, that are largely driven by excessive levels of oxidative stress (e.g., reactive oxygen species [ROS]). Emerging evidence suggests that several fundamental aging mechanisms (e.g., "hallmarks" of aging), including chronic low-grade inflammation, mitochondrial dysfunction, cellular senescence and deregulated nutrient sensing contribute to excessive ROS production and are common to both peripheral and cerebral vascular dysfunction. Therefore, targeting these mechanisms to reduce ROS-related oxidative stress and improve peripheral and/or cerebral vascular function may be a promising strategy to reduce dementia risk with aging. Investigating how certain lifestyle strategies (e.g., aerobic exercise and diet modulation) and/or select pharmacological agents (natural and synthetic) intersect with aging "hallmarks" to promote peripheral and/or cerebral vascular health represent a viable option for reducing dementia risk with aging. Therefore, the primary purpose of this review is to explore mechanistic links among peripheral vascular dysfunction, cerebral vascular dysfunction, and reduced brain health with aging. Such insight and assessments of non-invasive measures of peripheral and cerebral vascular health with aging might provide a new approach for assessing dementia risk in older adults.
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Affiliation(s)
- Devin Wahl
- Department of Health and Exercise Science and Center for Healthy Aging, Colorado State University, Fort Collins, CO 80523, USA
| | - Zachary S. Clayton
- University of Colorado Anschutz Medical Campus, Department of Medicine, Division of Geriatric Medicine, Aurora, CO 80045, USA
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Eddy AC, Rajakumar A, Spradley FT, Granger JP, Rana S. Luteolin prevents TNF-α-induced NF-κB activation and ROS production in cultured human placental explants and endothelial cells. Placenta 2024; 145:65-71. [PMID: 38096686 PMCID: PMC10872317 DOI: 10.1016/j.placenta.2023.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/22/2023] [Accepted: 12/04/2023] [Indexed: 01/12/2024]
Abstract
INTRODUCTION Preeclampsia (PE) is a serious hypertensive pregnancy disorder and a leading cause of maternal and perinatal morbidity and mortality. Despite the prevalence and complications, there are no approved therapeutics to relieve PE symptoms. Inflammation, oxidative stress, and angiogenic imbalance have been shown to contribute to the PE pathophysiology, though there is a lack of understanding in how best to target these pathways in PE. We recently demonstrated that the bioflavonoid luteolin is a potent inhibitor of the anti-angiogenic and pro-hypertensive soluble fms-like tyrosine kinase 1 (sFlt-1), and here we aimed to determine if luteolin was also capable of reducing inflammation and oxidative stress pathways. METHODS Tumor necrosis factor (TNF)-α, which is upregulated in PE, was utilized to stimulate these pathways in human placental explants and endothelial cells. Endothelin-1 (ET-1) and interleukin (IL)-6 in the media from explants and cells were measured via ELISA, and NF-κB localization and reactive oxygen species were detected via fluorescence microscopy. RESULTS Pretreatment with luteolin demonstrated significant reductions in NF-κB activation, reactive oxygen species, superoxide, and IL-6 and ET-1 expression in endothelial cells. We also saw a significant reduction in phosphorylation of NF-κB in human placental explants. DISCUSSION These data demonstrate that luteolin inhibits pathways implicated in the development of PE and should be explored further for its potential as a PE therapeutic.
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Affiliation(s)
- Adrian C Eddy
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago, IL, USA
| | | | - Frank T Spradley
- Department of Surgery and Department of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Joey P Granger
- Department of Physiology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Sarosh Rana
- Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Chicago, IL, USA.
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Engin A. Endothelial Dysfunction in Obesity and Therapeutic Targets. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:489-538. [PMID: 39287863 DOI: 10.1007/978-3-031-63657-8_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter β, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Moreau KL, Clayton ZS, DuBose LE, Rosenberry R, Seals DR. Effects of regular exercise on vascular function with aging: Does sex matter? Am J Physiol Heart Circ Physiol 2024; 326:H123-H137. [PMID: 37921669 PMCID: PMC11208002 DOI: 10.1152/ajpheart.00392.2023] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/11/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
Vascular aging, featuring endothelial dysfunction and large elastic artery stiffening, is a major risk factor for the development of age-associated cardiovascular diseases (CVDs). Vascular aging is largely mediated by an excessive production of reactive oxygen species (ROS) and increased inflammation leading to reduced bioavailability of the vasodilatory molecule nitric oxide and remodeling of the arterial wall. Other cellular mechanisms (i.e., mitochondrial dysfunction, impaired stress response, deregulated nutrient sensing, cellular senescence), termed "hallmarks" or "pillars" of aging, may also contribute to vascular aging. Gonadal aging, which largely impacts women but also impacts some men, modulates the vascular aging process. Regular physical activity, including both aerobic and resistance exercise, is a first-line strategy for reducing CVD risk with aging. Although exercise is an effective intervention to counter vascular aging, there is considerable variation in the vascular response to exercise training with aging. Aerobic exercise improves large elastic artery stiffening in both middle-aged/older men and women and enhances endothelial function in middle-aged/older men by reducing oxidative stress and inflammation and preserving nitric oxide bioavailability; however, similar aerobic exercise training improvements are not consistently observed in estrogen-deficient postmenopausal women. Sex differences in adaptations to exercise may be related to gonadal aging and declines in estrogen in women that influence cellular-molecular mechanisms, disconnecting favorable signaling in the vasculature induced by exercise training. The present review will summarize the current state of knowledge on vascular adaptations to regular aerobic and resistance exercise with aging, the underlying mechanisms involved, and the moderating role of biological sex.
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Affiliation(s)
- Kerrie L Moreau
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Eastern Colorado Health Care System, Geriatric Research Education and Clinical Center, Aurora, Colorado, United States
| | - Zachary S Clayton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Lyndsey E DuBose
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Ryan Rosenberry
- Division of Geriatric Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
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Jouabadi SM, Ataabadi EA, Golshiri K, Bos D, Stricker BHC, Danser AHJ, Mattace-Raso F, Roks AJM. Clinical Impact and Mechanisms of Nonatherosclerotic Vascular Aging: The New Kid to Be Blocked. Can J Cardiol 2023; 39:1839-1858. [PMID: 37495207 DOI: 10.1016/j.cjca.2023.07.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/07/2023] [Accepted: 07/20/2023] [Indexed: 07/28/2023] Open
Abstract
Ischemic cardiovascular disease and stroke remain the leading cause of global morbidity and mortality. During aging, protective mechanisms in the body gradually deteriorate, resulting in functional, structural, and morphologic changes that affect the vascular system. Because atherosclerotic plaques are not always present along with these alterations, we refer to this kind of vascular aging as nonatherosclerotic vascular aging (NAVA). To maintain proper vascular function during NAVA, it is important to preserve intracellular signalling, prevent inflammation, and block the development of senescent cells. Pharmacologic interventions targeting these components are potential therapeutic approaches for NAVA, with a particular emphasis on inflammation and senescence. This review provides an overview of the pathophysiology of vascular aging and explores potential pharmacotherapies that can improve the function of aged vasculature, focusing on NAVA.
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Affiliation(s)
- Soroush Mohammadi Jouabadi
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Ehsan Ataei Ataabadi
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Keivan Golshiri
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Daniel Bos
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Bruno H C Stricker
- Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - A H Jan Danser
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Francesco Mattace-Raso
- Division of Geriatric Medicine, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Anton J M Roks
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
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Blaj LA, Cucu AI, Tamba BI, Turliuc MD. The Role of the NF-kB Pathway in Intracranial Aneurysms. Brain Sci 2023; 13:1660. [PMID: 38137108 PMCID: PMC10871091 DOI: 10.3390/brainsci13121660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/25/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
The pathophysiology of intracranial aneurysms (IA) has been proven to be closely linked to hemodynamic stress and inflammatory pathways, most notably the NF-kB pathway. Therefore, it is a potential target for therapeutic intervention. In the present review, we investigated alterations in the vascular smooth muscle cells (VSMCs), extracellular matrix, and endothelial cells by the mediators implicated in the NF-kB pathway that lead to the formation, growth, and rupture of IAs. We also present an overview of the NF-kB pathway, focusing on stimuli and transcriptional targets specific to IAs, as well as a summary of the current strategies for inhibiting NF-kB activation in IAs. Our report adds to previously reported data and future research directions for treating IAs using compounds that can suppress inflammation in the vascular wall.
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Affiliation(s)
- Laurentiu Andrei Blaj
- Department of Neurosurgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.A.B.); (M.D.T.)
- “Prof. Dr. N. Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania
| | - Andrei Ionut Cucu
- “Prof. Dr. N. Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania
- Faculty of Medicine and Biological Sciences, University Stefan cel Mare of Suceava, 720229 Suceava, Romania
| | - Bogdan Ionel Tamba
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Pharmacology, Clinical Pharmacology and Algesiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Mihaela Dana Turliuc
- Department of Neurosurgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.A.B.); (M.D.T.)
- “Prof. Dr. N. Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania
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10
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Abdellatif M, Rainer PP, Sedej S, Kroemer G. Hallmarks of cardiovascular ageing. Nat Rev Cardiol 2023; 20:754-777. [PMID: 37193857 DOI: 10.1038/s41569-023-00881-3] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/21/2023] [Indexed: 05/18/2023]
Abstract
Normal circulatory function is a key determinant of disease-free life expectancy (healthspan). Indeed, pathologies affecting the cardiovascular system, which are growing in prevalence, are the leading cause of global morbidity, disability and mortality, whereas the maintenance of cardiovascular health is necessary to promote both organismal healthspan and lifespan. Therefore, cardiovascular ageing might precede or even underlie body-wide, age-related health deterioration. In this Review, we posit that eight molecular hallmarks are common denominators in cardiovascular ageing, namely disabled macroautophagy, loss of proteostasis, genomic instability (in particular, clonal haematopoiesis of indeterminate potential), epigenetic alterations, mitochondrial dysfunction, cell senescence, dysregulated neurohormonal signalling and inflammation. We also propose a hierarchical order that distinguishes primary (upstream) from antagonistic and integrative (downstream) hallmarks of cardiovascular ageing. Finally, we discuss how targeting each of the eight hallmarks might be therapeutically exploited to attenuate residual cardiovascular risk in older individuals.
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Affiliation(s)
- Mahmoud Abdellatif
- Department of Cardiology, Medical University of Graz, Graz, Austria.
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
- BioTechMed Graz, Graz, Austria.
| | - Peter P Rainer
- Department of Cardiology, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Simon Sedej
- Department of Cardiology, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
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Freeberg KA, Ludwig KR, Chonchol M, Seals DR, Rossman MJ. NAD +-boosting compounds enhance nitric oxide production and prevent oxidative stress in endothelial cells exposed to plasma from patients with COVID-19. Nitric Oxide 2023; 140-141:1-7. [PMID: 37657532 PMCID: PMC10840929 DOI: 10.1016/j.niox.2023.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/10/2023] [Accepted: 08/30/2023] [Indexed: 09/03/2023]
Abstract
SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), induces vascular endothelial dysfunction, but the mechanisms are unknown. We tested the hypothesis that the "circulating milieu" (plasma) of patients with COVID-19 would cause endothelial cell dysfunction (characterized by lower nitric oxide (NO) production), which would be linked to greater reactive oxygen species (ROS) bioactivity and depletion of the critical metabolic co-substrate, nicotinamide adenine dinucleotide (NAD+). We also investigated if treatment with NAD+-boosting compounds would prevent COVID-19-induced reductions in endothelial cell NO bioavailability and oxidative stress. Human aortic endothelial cells (HAECs) were exposed to plasma from men and women (age 18-85 years) who were hospitalized and tested positive (n = 34; 20 M) or negative (n = 13; 10 M) for COVID-19. HAECs exposed to plasma from patients with COVID-19 also were co-incubated with NAD+ precursors nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). Acetylcholine-stimulated NO production was 27% lower and ROS bioactivity was 54% higher in HAECs exposed to plasma from patients with COVID-19 (both p < 0.001 vs. control); these responses were independent of age and sex. NAD+ concentrations were 30% lower in HAECs exposed to plasma from patients with COVID-19 (p = 0.001 vs. control). Co-incubation with NR abolished COVID-19-induced reductions in NO production and oxidative stress (both p > 0.05 vs. control). Co-treatment with NMN produced similar results. Our findings suggest the circulating milieu of patients with COVID-19 promotes endothelial cell dysfunction, characterized by lower NO bioavailability, greater ROS bioactivity, and NAD+ depletion. Supplementation with NAD+ precursors may exert a protective effect against COVID-19-evoked endothelial cell dysfunction and oxidative stress.
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Affiliation(s)
- Kaitlin A Freeberg
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Katelyn R Ludwig
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Matthew J Rossman
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, 80309, USA.
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12
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Demirdağ F, Yavuzer S, Cengiz M, Yavuzer H, Kara Z, Ayvacı A, Avcı S, Yürüyen M, Uzun H, Altıparmak MR, Döventaş A, Erdinçler DS. The Role of NF-κB, PPAR-α, and PPAR-γ in Older Adults with Metabolic Syndrome. Horm Metab Res 2023; 55:733-740. [PMID: 37308136 DOI: 10.1055/a-2109-1958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The etiopathogenesis of metabolic syndrome (MetS) has not been fully understood yet, and chronic low-grade inflammation is thought to be associated with the development of complications related to MetS. We aimed to investigate the role of Nuclear factor Kappa B ( NF-κB ), Peroxisome Proliferator-Activated Receptor- α and γ (PPAR-α, and PPAR-γ) which are the main markers of inflammation in older adults with MetS. A total of 269 patients aged≥18, 188 patients with MetS who met the diagnostic criteria of the International Diabetes Federation, and 81 controls who applied to geriatrics and general internal medicine outpatient clinics for various reasons were included in the study. Patients were separated into four groups: young with MetS (< 60, n=76), elderly with MetS (≥60, n=96), young control (< 60, n=31), elderly controls (≥60, n=38). Carotid intima-media thickness (CIMT) and NF-κB , PPAR-α, and PPAR-γ plasma levels were measured in all of the participants. Age and sex distribution were similar between MetS and control groups. C-reactive protein (CRP), NF-κB levels (p=0.001) and CIMT (p<0,001) of MetS group were significantly higher than in the control groups. On the other hand, the PPAR-γ (p=0.008) and PPAR-α (p=0.003) levels were significantly lower in MetS. ROC analysis revealed that the NF-κB, PPAR-α, and PPAR-γ could be used to indicate MetS in younger adults (AUC: 0.735, p<0.000; AUC: 0.653, p=0.003), whereas it could not be an indicator in older adults (AUC: 0.617, p=0.079; AUC:0.530, p=0.613). It seems that these markers have important roles in MetS-related inflammation. In our results, suggest that the indicator feature of NF-κB , PPAR-α and PPAR-γ in recognizing MetS in young individuals is lost in older adults with Mets.
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Affiliation(s)
- Filiz Demirdağ
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
- Division of Geriatrics, Department of Internal Medicine, Istanbul Medeniyet University, School of Medicine Istanbul, Turkey
| | - Serap Yavuzer
- Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Mahir Cengiz
- Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Hakan Yavuzer
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Zehra Kara
- Division of Endocrinology, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Adnan Ayvacı
- Department of Radiology, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Suna Avcı
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Mehmet Yürüyen
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Hafize Uzun
- Department of Biochemistry, Istanbul Atlas University, School of Medicine, Istanbul, Turkey
| | - Mehmet Rıza Altıparmak
- Division of Nephrology, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Alper Döventaş
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
| | - Deniz Suna Erdinçler
- Division of Geriatrics, Department of Internal Medicine, Istanbul University-Cerrahpasa, School of Medicine, Istanbul, Turkey
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13
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Xiang X, Xie L, Lin J, Pare R, Huang G, Huang J, Wang Y, Song S, Ruan Y. Estrogen receptor alpha mediates 17β-estradiol, up-regulates autophagy and alleviates hydrogen peroxide-induced vascular senescence. Biogerontology 2023; 24:783-799. [PMID: 36683095 DOI: 10.1007/s10522-023-10015-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 01/10/2023] [Indexed: 01/24/2023]
Abstract
Atherosclerosis threatens human health by developing cardiovascular diseases, the deadliest disease world widely. The major mechanism contributing to the formation of atherosclerosis is mainly due to vascular endothelial cell (VECs) senescence. We have shown that 17β-estradiol (17β-E2) may protect VECs from senescence by upregulating autophagy. However, little is known about how 17β-E2 activates the autophagy pathway to alleviate cellular senescence. Therefore, the aim of this study is to determine the role of estrogen receptor (ER) α and β in the effects of 17β-E2 on vascular autophagy and aging through in vitro and in vivo models. Hydrogen peroxide (H2O2) was used to establish Human Umbilical Vein Endothelial Cells (HUVECs) senescence. Autophagy activity was measured through immunofluorescence and immunohistochemistry staining of light chain 3 (LC3) expression. Inhibition of ER activity was established using shRNA gene silencing and ER antagonist. Compared with ER-β knockdown, we found that knockdown of ER-α resulted in a significant increase in the extent of HUVEC senescence and senescence-associated secretory phenotype (SASP) secretion. ER-α-specific shRNA was found to reduce 17β-E2-induced autophagy, promote HUVEC senescence, disrupt the morphology of HUVECs, and increase the expression of Rb dephosphorylation and SASP. These in vitro findings were found consistent with the in vivo results. In conclusion, our data suggest that 17β-E2 activates the activity of ER-α and then increases the formation of autophagosomes (LC3 high expression) and decreases the fusion of lysosomes with autophagic vesicles (P62 low expression), which in turn serves to decrease the secretion of SASP caused by H2O2 and consequently inhibit H2O2-induced senescence in HUVEC cells.
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Affiliation(s)
- Xiuting Xiang
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - LiangZhen Xie
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jieqi Lin
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Rahmawati Pare
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Malaysia
| | - Guanshen Huang
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jianming Huang
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yuyan Wang
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Shicong Song
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yunjun Ruan
- Department of Geriatrics, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
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14
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Mengozzi A, de Ciuceis C, Dell'oro R, Georgiopoulos G, Lazaridis A, Nosalski R, Pavlidis G, Tual-Chalot S, Agabiti-Rosei C, Anyfanti P, Camargo LL, Dąbrowska E, Quarti-Trevano F, Hellmann M, Masi S, Mavraganis G, Montezano AC, Rios FJ, Winklewski PJ, Wolf J, Costantino S, Gkaliagkousi E, Grassi G, Guzik TJ, Ikonomidis I, Narkiewicz K, Paneni F, Rizzoni D, Stamatelopoulos K, Stellos K, Taddei S, Touyz RM, Triantafyllou A, Virdis A. The importance of microvascular inflammation in ageing and age-related diseases: a position paper from the ESH working group on small arteries, section of microvascular inflammation. J Hypertens 2023; 41:1521-1543. [PMID: 37382158 DOI: 10.1097/hjh.0000000000003503] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological systems targeted by environmental stressors and consequently involved in the development and progression of ageing and age-related disease. Microvascular dysfunction, if not targeted, leads to a steady derangement of the phenotype, which cumulates comorbidities and eventually results in a nonrescuable, very high-cardiovascular risk. Along the broad spectrum of pathologies, both shared and distinct molecular pathways and pathophysiological alteration are involved in the disruption of microvascular homeostasis, all pointing to microvascular inflammation as the putative primary culprit. This position paper explores the presence and the detrimental contribution of microvascular inflammation across the whole spectrum of chronic age-related diseases, which characterise the 21st-century healthcare landscape. The manuscript aims to strongly affirm the centrality of microvascular inflammation by recapitulating the current evidence and providing a clear synoptic view of the whole cardiometabolic derangement. Indeed, there is an urgent need for further mechanistic exploration to identify clear, very early or disease-specific molecular targets to provide an effective therapeutic strategy against the otherwise unstoppable rising prevalence of age-related diseases.
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Affiliation(s)
- Alessandro Mengozzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Health Science Interdisciplinary Center, Scuola Superiore Sant'Anna, Pisa
| | - Carolina de Ciuceis
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia
| | - Raffaella Dell'oro
- Clinica Medica, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Georgios Georgiopoulos
- Angiology and Endothelial Pathophysiology Unit, Department of Clinical Therapeutics, Medical School, National and Kapodistrian University of Athens, Athens
| | - Antonios Lazaridis
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece
| | - Ryszard Nosalski
- Centre for Cardiovascular Sciences; Queen's Medical Research Institute; University of Edinburgh, University of Edinburgh, Edinburgh, UK
- Department of Internal Medicine
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - George Pavlidis
- Preventive Cardiology Laboratory and Clinic of Cardiometabolic Diseases, 2 Cardiology Department, Attikon Hospital, Athens
- Medical School, National and Kapodistrian University of Athens, Greece
| | - Simon Tual-Chalot
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | | | - Panagiota Anyfanti
- Second Medical Department, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Livia L Camargo
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
- Research Institute of the McGill University Health Centre (RI-MUHC), McGill University, Montreal, Canada
| | - Edyta Dąbrowska
- Department of Hypertension and Diabetology, Center of Translational Medicine
- Center of Translational Medicine
| | - Fosca Quarti-Trevano
- Clinica Medica, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Marcin Hellmann
- Department of Cardiac Diagnostics, Medical University, Gdansk, Poland
| | - Stefano Masi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Institute of Cardiovascular Science, University College London, London, UK
| | - Georgios Mavraganis
- Angiology and Endothelial Pathophysiology Unit, Department of Clinical Therapeutics, Medical School, National and Kapodistrian University of Athens, Athens
| | - Augusto C Montezano
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
- Research Institute of the McGill University Health Centre (RI-MUHC), McGill University, Montreal, Canada
| | - Francesco J Rios
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
- Research Institute of the McGill University Health Centre (RI-MUHC), McGill University, Montreal, Canada
| | | | - Jacek Wolf
- Department of Hypertension and Diabetology, Center of Translational Medicine
| | - Sarah Costantino
- Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- University Heart Center, Cardiology, University Hospital Zurich
| | - Eugenia Gkaliagkousi
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece
| | - Guido Grassi
- Clinica Medica, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Tomasz J Guzik
- Centre for Cardiovascular Sciences; Queen's Medical Research Institute; University of Edinburgh, University of Edinburgh, Edinburgh, UK
- Department of Internal Medicine
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, Krakow, Poland
| | - Ignatios Ikonomidis
- Preventive Cardiology Laboratory and Clinic of Cardiometabolic Diseases, 2 Cardiology Department, Attikon Hospital, Athens
- Medical School, National and Kapodistrian University of Athens, Greece
| | | | - Francesco Paneni
- Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- University Heart Center, Cardiology, University Hospital Zurich
- Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Damiano Rizzoni
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia
- Division of Medicine, Spedali Civili di Brescia, Montichiari, Brescia, Italy
| | - Kimon Stamatelopoulos
- Angiology and Endothelial Pathophysiology Unit, Department of Clinical Therapeutics, Medical School, National and Kapodistrian University of Athens, Athens
| | - Konstantinos Stellos
- Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
- Department of Cardiovascular Research, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University
- German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung, DZHK), Heidelberg/Mannheim Partner Site
- Department of Cardiology, University Hospital Mannheim, Heidelberg University, Manheim, Germany
| | - Stefano Taddei
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Rhian M Touyz
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
- Research Institute of the McGill University Health Centre (RI-MUHC), McGill University, Montreal, Canada
| | - Areti Triantafyllou
- Third Department of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou Hospital, Thessaloniki, Greece
| | - Agostino Virdis
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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15
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Tahsin CT, Michopoulos V, Powers A, Park J, Ahmed Z, Cullen K, Jenkins NDM, Keller-Ross M, Fonkoue IT. Sleep efficiency and PTSD symptom severity predict microvascular endothelial function and arterial stiffness in young, trauma-exposed women. Am J Physiol Heart Circ Physiol 2023; 325:H739-H750. [PMID: 37505472 PMCID: PMC10642999 DOI: 10.1152/ajpheart.00169.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 07/13/2023] [Accepted: 07/28/2023] [Indexed: 07/29/2023]
Abstract
Posttraumatic stress disorder (PTSD) is linked to sleep disturbances and significantly higher risk of developing cardiovascular disease (CVD). Furthermore, vascular dysfunction and sleep are independently associated with CVD. Uncovering the link between PTSD symptom severity, sleep disturbances, and vascular function could shine a light on mechanisms of CVD risk in trauma-exposed young women. The purpose of the present study was to investigate the individual and combined effects of sleep efficiency and PTSD symptom severity on vascular function. We recruited 60 otherwise healthy women [age, 26 ± 7 yr and body mass index (BMI), 27.7 ± 6.5 kg/m2] who had been exposed to trauma. We objectively quantified sleep efficiency (SE) using actigraphy, microvascular endothelial function via Framingham reactive hyperemia index (fRHI), and arterial stiffness via pulse-wave velocity (PWV). PTSD symptom severity was assessed using the PTSD checklist for fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (PCL5). PWV was correlated with age (r = 0.490, P < 0.001) and BMI (r = 0.484, P < 0.001). In addition, fRHI was positively correlated with SE (r = 0.409, P = 0.001) and negatively correlated with PTSD symptoms (r = -0.382, P = 0.002). To explore the predictive value of SE and PTSD symptoms on PWV and fRHI, we conducted two multivariate linear regression models. The model predicting PWV was significant (R2 = 0.584, P < 0.001) with age, BMI, blood pressure, and SE emerging as predictors. Likewise, the model predicting fRHI was significant (R2 = 0.360, P < 0.001) with both PTSD symptoms and SE as significant predictors. Our results suggest that although PTSD symptoms mainly impact microvascular endothelial function, sleep efficiency is additionally associated with arterial stiffness in young trauma-exposed women, after controlling for age and BMI.NEW & NOTEWORTHY This is the first study to investigate the individual and combined impacts of objective sleep and PTSD symptoms severity on arterial stiffness and microvascular endothelial function in young premenopausal women. We report that in young trauma-exposed women, although low sleep efficiency is associated with overall vascular function (i.e., microvascular endothelial function and arterial stiffness), the severity of PTSD symptoms is specifically associated with microvascular endothelial function, after accounting for age and body mass index.
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Affiliation(s)
- Chowdhury Tasnova Tahsin
- Division of Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Division of Rehabilitation Science, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
| | - Vasiliki Michopoulos
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Abigail Powers
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Jeanie Park
- Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
- Department of Veterans Affairs, Research Service Line, Atlanta Veterans Affairs Healthcare Systems, Decatur, Georgia, United States
| | - Zynab Ahmed
- Division of Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Division of Rehabilitation Science, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
| | - Kathryn Cullen
- Department of Psychiatry, University of Minnesota Medical School, Minneapolis, Minnesota, United States
| | - Nathaniel D M Jenkins
- Department of Health and Human Physiology, University of Iowa, Iowa City, Iowa, United States
- Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa, United States
| | - Manda Keller-Ross
- Division of Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Division of Rehabilitation Science, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
| | - Ida T Fonkoue
- Division of Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Division of Rehabilitation Science, Department of Rehabilitation Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States
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16
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Brewster LM, Bain AR, Garcia VP, DeSouza NM, Tymko MM, Greiner JJ, Ainslie PN. Global REACH 2018: High Altitude-Related Circulating Extracellular Microvesicles Promote a Proinflammatory Endothelial Phenotype In Vitro. High Alt Med Biol 2023; 24:223-229. [PMID: 37504958 DOI: 10.1089/ham.2023.0013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023] Open
Abstract
Brewster, L. Madden, Anthony R. Bain, Vinicius P. Garcia, Noah M. DeSouza, Michael M. Tymko, Jared J. Greiner, and Philip N. Ainslie. Global REACH 2018: high altitude-related circulating extracellular microvesicles promote a proinflammatory endothelial phenotype in vitro. High Alt Med Biol. 24:223-229, 2023. Introduction: Ascent to high altitude (HA) can induce vascular dysfunction by promoting a proinflammatory endothelial phenotype. Circulating microvesicles (MVs) can mediate the vascular endothelium and inflammation. It is unclear whether HA-related MVs are associated with endothelial inflammation. Objectives: We tested the hypothesis that MVs derived from ascent to HA induce a proinflammatory endothelial phenotype. Methods: Ten healthy adults (8 M/2 F; age: 28 ± 2 years) residing at sea level (SL) were studied before and 4-6 days after rapid ascent to HA (4,300 m). MVs were isolated and enumerated from plasma by centrifugation and flow cytometry. Human umbilical vein endothelial cells were treated with MVs collected from each subject at SL (MV-SL) and at HA (MV-HA). Results: Circulating MV number significantly increased at HA (26,637 ± 3,315 vs. 19,388 ± 1,699). Although intracellular expression of total nuclear factor kappa beta (NF-κB; 83.4 ± 6.7 arbitrary units [AU] vs. 90.2 ± 6.9 AU) was not affected, MV-HA resulted in ∼55% higher (p < 0.05) active NF-κB (129.6 ± 19.8 AU vs. 90.7 ± 10.5 AU) expression compared with MV-SL. In addition, MV-HA induced higher interleukin (IL)-6 (63.9 ± 3.9 pg/ml vs. 53.3 ± 3.6 pg/ml) and IL-8 (140.2 ± 3.6 pg/ml vs. 120.7 ± 3.8 pg/ml) release compared with MV-SL, which was blunted with NF-κB blockade. Conclusions: Circulating extracellular MVs increase at HA and induce endothelial inflammation, potentially contributing to altitude-related vascular dysfunction.
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Affiliation(s)
- L Madden Brewster
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
- Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences, Faculty of Health and Social Development, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Anthony R Bain
- Department of Kinesiology, University of Windsor, Windsor, Ontario, Canada
| | - Vinicius P Garcia
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Noah M DeSouza
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Michael M Tymko
- Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences, Faculty of Health and Social Development, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - Jared J Greiner
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Philip N Ainslie
- Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences, Faculty of Health and Social Development, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
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17
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Kumar R, Kumar U, Trivedi S. Comparison of Risk Factors for Erectile Dysfunction (ED) in Type 2 Diabetics and Nondiabetics: A Retrospective Observational Study. Cureus 2023; 15:e44576. [PMID: 37790032 PMCID: PMC10545003 DOI: 10.7759/cureus.44576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND AND AIMS We aim to compare the various risk factors for erectile dysfunction (ED) in type 2 diabetes mellitus (DM) and nondiabetic patients. MATERIALS AND METHODS We retrospectively collected and evaluated the data of 175 OPD patients with ED. We included 138 patients of ED from endocrinology and urology OPD after exclusion. ED was assessed by using a questionnaire adapted from the abridged five-item version of the International Index of Erectile Function (IIEF-5) score. RESULTS A total of 96 (69.56%) were diabetic, and 42 (30.43%) were nondiabetic. The majority of patients (62.31 %) were in the age group of 40-60 years. Thirty-nine (28.26%) were alcoholics, and 55 (40%) were smokers. The average duration of diabetes was 6.6±1.5 years. Hypertension was present in 49 (35.5%). Diabetic patients were significantly older (47.9±8.2 vs. 40.2±7.6 years, p=0.0001) and obese (BMI (kg/m2), 27.3±5.4 vs. 24.6±3.9, p=0.004). Waist circumference in diabetics was 95.3±10.9, as compared to nondiabetics, which was 89.6±9.2 cm (p=0.0037). The IIEF-5 score was significantly lower in diabetic subjects in comparison to nondiabetics (9.4±3.2 vs. 12.1±3.6 p=0.0001). Moderate-to-severe ED was more common in diabetic patients (76%) in comparison to nondiabetics (59.5%). The prevalence of mild and mild-to-moderate ED was 11.45 % and 12.5 % in diabetic patients in comparison to 16.7% and 23.5% in nondiabetics, respectively. The prevalence of hypertension and coronary artery was higher in diabetics in comparison with nondiabetics. Hypertension was significantly higher in diabetic patients with ED (42.7% vs. 19.04%, p=0.0075), but coronary artery disease was not statistically significant (8.3% vs. 2.3%, p=0.1925). LH (2.6±0.7 vs. 3.5±0, p=0.0001) and testosterone (312.1±110.7 vs. 367.8±115.1, p=0.0081) were significantly lower in diabetics in comparison to nondiabetics. CONCLUSIONS The IIEF-5 score was lower in diabetic cases as compared to those without diabetes. The factors that significantly contributed to ED in type 2 DM patients, as compared to nondiabetic patients, were age, BMI, waist circumference, hypertension, poor glycemic control, LH, and testosterone levels.
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Affiliation(s)
- Ritesh Kumar
- Department of Endocrinology, Diabetes and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, IND
| | - Ujwal Kumar
- Department of Urology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, IND
| | - Sameer Trivedi
- Department of Urology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, IND
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18
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Minjares M, Wu W, Wang JM. Oxidative Stress and MicroRNAs in Endothelial Cells under Metabolic Disorders. Cells 2023; 12:1341. [PMID: 37174741 PMCID: PMC10177439 DOI: 10.3390/cells12091341] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/28/2023] [Accepted: 05/06/2023] [Indexed: 05/15/2023] Open
Abstract
Reactive oxygen species (ROS) are radical oxygen intermediates that serve as important second messengers in signal transduction. However, when the accumulation of these molecules exceeds the buffering capacity of antioxidant enzymes, oxidative stress and endothelial cell (EC) dysfunction occur. EC dysfunction shifts the vascular system into a pro-coagulative, proinflammatory state, thereby increasing the risk of developing cardiovascular (CV) diseases and metabolic disorders. Studies have turned to the investigation of microRNA treatment for CV risk factors, as these post-transcription regulators are known to co-regulate ROS. In this review, we will discuss ROS pathways and generation, normal endothelial cell physiology and ROS-induced dysfunction, and the current knowledge of common metabolic disorders and their connection to oxidative stress. Therapeutic strategies based on microRNAs in response to oxidative stress and microRNA's regulatory roles in controlling ROS will also be explored. It is important to gain an in-depth comprehension of the mechanisms generating ROS and how manipulating these enzymatic byproducts can protect endothelial cell function from oxidative stress and prevent the development of vascular disorders.
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Affiliation(s)
- Morgan Minjares
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA;
| | - Wendy Wu
- Vera P Shiffman Medical Library, Wayne State University, 320 E Canfield St., Detroit, MI 48201, USA;
| | - Jie-Mei Wang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA;
- Center for Molecular Medicine and Genetics, Wayne State University, 320 E Canfield St., Detroit, MI 48201, USA
- Barbara Ann Karmanos Cancer Institute, 4100 John R St., Detroit, MI 48201, USA
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Woolf EK, Terwoord JD, Litwin NS, Vazquez AR, Lee SY, Ghanem N, Michell KA, Smith BT, Grabos LE, Ketelhut NB, Bachman NP, Smith ME, Le Sayec M, Rao S, Gentile CL, Weir TL, Rodriguez-Mateos A, Seals DR, Dinenno FA, Johnson SA. Daily blueberry consumption for 12 weeks improves endothelial function in postmenopausal women with above-normal blood pressure through reductions in oxidative stress: a randomized controlled trial. Food Funct 2023; 14:2621-2641. [PMID: 36847333 DOI: 10.1039/d3fo00157a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Estrogen-deficient postmenopausal women have oxidative stress-mediated suppression of endothelial function that is exacerbated by high blood pressure. Previous research suggests blueberries may improve endothelial function through reductions in oxidative stress, while also exerting other cardiovascular benefits. The objective of this study was to examine the efficacy of blueberries to improve endothelial function and blood pressure in postmenopausal women with above-normal blood pressure, and to identify potential mechanisms for improvements in endothelial function. A randomized, double-blind, placebo-controlled, parallel-arm clinical trial was performed, where postmenopausal women aged 45-65 years with elevated blood pressure or stage 1-hypertension (total n = 43, endothelial function n = 32) consumed 22 g day-1 of freeze-dried highbush blueberry powder or placebo powder for 12 weeks. Endothelial function was assessed at baseline and 12 weeks through ultrasound measurement of brachial artery flow-mediated dilation (FMD) normalized to shear rate area under the curve (FMD/SRAUC) before and after intravenous infusion of a supraphysiologic dose of ascorbic acid to evaluate whether FMD improvements were mediated by reduced oxidative stress. Hemodynamics, arterial stiffness, cardiometabolic blood biomarkers, and plasma (poly)phenol metabolites were assessed at baseline and 4, 8, and 12 weeks, and venous endothelial cell protein expression was assessed at baseline and 12 weeks. Absolute FMD/SRAUC was 96% higher following blueberry consumption compared to baseline (p < 0.05) but unchanged in the placebo group (p > 0.05), and changes from baseline to 12 weeks were greater in the blueberry group than placebo (+1.09 × 10-4 ± 4.12 × 10-5vs. +3.82 × 10-6 ± 1.59 × 10-5, p < 0.03, respectively). The FMD/SRAUC response to ascorbic acid infusion was lower (p < 0.05) at 12 weeks compared to baseline in the blueberry group with no change in the placebo group (p > 0.05). The sum of plasma (poly)phenol metabolites increased at 4, 8, and 12 weeks in the blueberry group compared to baseline, and were higher than the placebo group (all p < 0.05). Increases in several plasma flavonoid and microbial metabolites were also noted. No major differences were found for blood pressure, arterial stiffness, blood biomarkers, or endothelial cell protein expression following blueberry consumption. These findings suggest daily consumption of freeze-dried blueberry powder for 12 weeks improves endothelial function through reduced oxidative stress in postmenopausal women with above-normal blood pressure. The clinical trial registry number is NCT03370991 (https://clinicaltrials.gov).
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Affiliation(s)
- Emily K Woolf
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Janée D Terwoord
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA
| | - Nicole S Litwin
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Allegra R Vazquez
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Sylvia Y Lee
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Nancy Ghanem
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Kiri A Michell
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Brayden T Smith
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Lauren E Grabos
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Nathaniel B Ketelhut
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA
| | - Nate P Bachman
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA
| | - Meghan E Smith
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA
| | - Melanie Le Sayec
- Department of Nutritional Sciences, School of Life Course and Population Sciences, King's College London, London, England, UK
| | - Sangeeta Rao
- Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Christopher L Gentile
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Tiffany L Weir
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
| | - Ana Rodriguez-Mateos
- Department of Nutritional Sciences, School of Life Course and Population Sciences, King's College London, London, England, UK
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado, Boulder, CO, USA
| | - Frank A Dinenno
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, USA
| | - Sarah A Johnson
- Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA.
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20
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Jiang J, Ni L, Zhang X, Gokulnath P, Vulugundam G, Li G, Wang H, Xiao J. Moderate-Intensity Exercise Maintains Redox Homeostasis for Cardiovascular Health. Adv Biol (Weinh) 2023; 7:e2200204. [PMID: 36683183 DOI: 10.1002/adbi.202200204] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/27/2022] [Indexed: 01/24/2023]
Abstract
It is well known that exercise is beneficial for cardiovascular health. Oxidative stress is the common pathological basis of many cardiovascular diseases. The overproduction of free radicals, both reactive oxygen species and reactive nitrogen species, can lead to redox imbalance and exacerbate oxidative damage to the cardiovascular system. Maintaining redox homeostasis and enhancing anti-oxidative capacity are critical mechanisms by which exercise protects against cardiovascular diseases. Moderate-intensity exercise is an effective means to maintain cardiovascular redox homeostasis. Moderate-intensity exercise reduces the risk of cardiovascular disease by improving mitochondrial function and anti-oxidative capacity. It also attenuates adverse cardiac remodeling and enhances cardiac function. This paper reviews the primary mechanisms of moderate-intensity exercise-mediated redox homeostasis in the cardiovascular system. Exploring the role of exercise-mediated redox homeostasis in the cardiovascular system is of great significance to the prevention and treatment of cardiovascular diseases.
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Affiliation(s)
- Jizong Jiang
- Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, 226011, China.,Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Lingyan Ni
- Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, 226011, China.,Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Xinxin Zhang
- Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, 226011, China.,Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Priyanka Gokulnath
- Cardiovascular Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | | | - Guoping Li
- Cardiovascular Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Hongyun Wang
- Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, 226011, China.,Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Junjie Xiao
- Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, 226011, China.,Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China
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21
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Association between atherogenic risk-modulating proteins and endothelium-dependent flow-mediated dilation in coronary artery disease patients. Eur J Appl Physiol 2023; 123:367-380. [PMID: 36305972 PMCID: PMC9894982 DOI: 10.1007/s00421-022-05040-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 09/04/2022] [Indexed: 02/06/2023]
Abstract
PURPOSE Endothelial dysfunction is an early and integral event in the development of atherosclerosis and coronary artery disease (CAD). Reduced NO bioavailability, oxidative stress, vasoconstriction, inflammation and senescence are all implicated in endothelial dysfunction. However, there are limited data examining associations between these pathways and direct in vivo bioassay measures of endothelial function in CAD patients. This study aimed to examine the relationships between in vivo measures of vascular function and the expression of atherogenic risk-modulating proteins in endothelial cells (ECs) isolated from the radial artery of CAD patients. METHODS Fifty-six patients with established CAD underwent trans-radial catheterization. Prior to catheterization, radial artery vascular function was assessed using a) flow-mediated dilation (FMD), and b) exercise-induced dilation in response to handgrip (HE%). Freshly isolated ECs were obtained from the radial artery during catheterization and protein content of eNOS, NAD(P)H oxidase subunit NOX2, NFκB, ET-1 and the senescence markers p53, p21 and p16 were evaluated alongside nitrotyrosine abundance and eNOS Ser1177 phosphorylation. RESULTS FMD was positively associated with eNOS Ser1177 phosphorylation (r = 0.290, P = 0.037), and protein content of p21 (r = 0.307, P = 0.027) and p16 (r = 0.426, P = 0.002). No associations were found between FMD and markers of oxidative stress, vasoconstriction or inflammation. In contrast to FMD, HE% was not associated with any of the EC proteins. CONCLUSION These data revealed a difference in the regulation of endothelium-dependent vasodilation measured in vivo between patients with CAD compared to previously reported data in subjects without a clinical diagnosis, suggesting that eNOS Ser1177 phosphorylation may be the key to maintain vasodilation in CAD patients.
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22
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Pacinella G, Ciaccio AM, Tuttolomondo A. Endothelial Dysfunction and Chronic Inflammation: The Cornerstones of Vascular Alterations in Age-Related Diseases. Int J Mol Sci 2022; 23:15722. [PMID: 36555364 PMCID: PMC9779461 DOI: 10.3390/ijms232415722] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Vascular diseases of the elderly are a topic of enormous interest in clinical practice, as they have great epidemiological significance and lead to ever-increasing healthcare expenditures. The mechanisms underlying these pathologies have been increasingly characterized over the years. It has emerged that endothelial dysfunction and chronic inflammation play a diriment role among the most relevant pathophysiological mechanisms. As one can easily imagine, various processes occur during aging, and several pathways undergo irreversible alterations that can promote the decline and aberrations that trigger the diseases above. Endothelial dysfunction and aging of circulating and resident cells are the main characteristics of the aged organism; they represent the framework within which an enormous array of molecular abnormalities occur and contribute to accelerating and perpetuating the decline of organs and tissues. Recognizing and detailing each of these dysfunctional pathways is helpful for therapeutic purposes, as it allows one to hypothesize the possibility of tailoring interventions to the damaged mechanism and hypothetically limiting the cascade of events that drive the onset of these diseases. With this paper, we have reviewed the scientific literature, analysing the pathophysiological basis of the vascular diseases of the elderly and pausing to reflect on attempts to interrupt the vicious cycle that connotes the diseases of aging, laying the groundwork for therapeutic reasoning and expanding the field of scientific research by moving from a solid foundation.
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Affiliation(s)
| | | | - Antonino Tuttolomondo
- Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (PROMISE) G. D’Alessandro, University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy
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23
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Wolf ST, Dillon GA, Alexander LM, Jablonski NG, Kenney WL. Skin pigmentation is negatively associated with circulating vitamin D concentration and cutaneous microvascular endothelial function. Am J Physiol Heart Circ Physiol 2022; 323:490-498. [PMID: 35930446 PMCID: PMC9448272 DOI: 10.1152/ajpheart.00309.2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/22/2022]
Abstract
Darkly pigmented individuals are at the greatest risk of hypovitaminosis D, which may result in microvascular endothelial dysfunction via reduced nitric oxide (NO) bioavailability and/or increased oxidative stress and inflammation. We investigated the associations among skin pigmentation (M-index; skin reflectance spectrophotometry), serum vitamin D concentration [25(OH)D], circulating inflammatory cytokine (TNF-α, IL-6, and IL-10) concentrations, and the NO contribution to local heating-induced cutaneous vasodilation (%NO-mediated vasodilation) in a diversely pigmented cohort of young adults. An intradermal microdialysis fiber was placed in the forearms of 33 healthy adults (14 men/19 women; 18-27 yr; M-index, 30-81 AU) for local delivery of pharmacological agents. Lactated Ringer's solution was perfused through the fiber during local heating-induced (39°C) cutaneous vasodilation. After attaining stable elevated blood flow, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibiter) was infused to quantify %NO-mediated vasodilation. Red cell flux was measured (laser-Doppler flowmetry; LDF) and cutaneous vascular conductance (CVC = LDF/MAP) was normalized to maximal (%CVCmax; 28 mM sodium nitroprusside + 43°C). Serum [25(OH)D] and circulating cytokines were analyzed by ELISA and multiplex assay, respectively. M-index was negatively associated with [25(OH)D] (r = -0.57, P < 0.0001) and %NO-mediated vasodilation (r = -0.42, P = 0.02). Serum[25(OH)D] was positively related to %NO (r = 0.41, P = 0.02). Controlling for [25(OH)D] weakened the association between M-index and %NO-mediated dilation (P = 0.16, r = -0.26). There was a negative curvilinear relation between [25(OH)D] and circulating IL-6 (r = -0.56, P < 0.001), but not TNF-α or IL-10 (P ≥ 0.14). IL-6 was not associated with %NO-mediated vasodilation (P = 0.44). These data suggest that vitamin D insufficiency/deficiency may contribute to reduced microvascular endothelial function in healthy, darkly pigmented young adults.NEW & NOTEWORTHY Endothelial dysfunction, an antecedent to hypertension and overt CVD, is commonly observed in otherwise healthy Black adults, although the underlying causes remain unclear. We show that reduced vitamin D availability with increasing degrees of skin pigmentation is associated with reduced microvascular endothelial function, independent of race or ethnicity, in healthy young adults. Greater prevalence of vitamin D deficiency in more darkly pigmented individuals may predispose them to increased risk of endothelial dysfunction.
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Affiliation(s)
- S Tony Wolf
- Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania
| | - Gabrielle A Dillon
- Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania
| | - Lacy M Alexander
- Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania
- Graduate Program in Physiology, The Pennsylvania State University, University Park, Pennsylvania
| | - Nina G Jablonski
- Department of Anthropology, The Pennsylvania State University, University Park, Pennsylvania
| | - W Larry Kenney
- Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania
- Graduate Program in Physiology, The Pennsylvania State University, University Park, Pennsylvania
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24
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Terwoord JD, Beyer AM, Gutterman DD. Endothelial dysfunction as a complication of anti-cancer therapy. Pharmacol Ther 2022; 237:108116. [PMID: 35063569 PMCID: PMC9294076 DOI: 10.1016/j.pharmthera.2022.108116] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 12/16/2021] [Accepted: 01/12/2022] [Indexed: 12/14/2022]
Abstract
Recent strides in anti-cancer therapeutics have improved longevity and led to a growing population of cancer survivors, who are increasingly likely to die of other causes. Treatment-induced cardiotoxicity is a complication of several therapeutic agents with acute and long-term consequences for cancer patients. Vascular endothelial dysfunction is a precursor and hallmark of ischemic coronary disease and may play a role in anti-cancer therapy-induced cardiotoxicity. This review summarizes clinical evidence for endothelial dysfunction following anti-cancer therapy and extends the discussion to include the impact of therapeutic agents on conduit arteries and the microcirculation. We highlight the role of innate immune system activation and cross-talk between inflammation and oxidative stress as pathogenic mechanisms underlying anti-cancer therapy-induced vascular toxicity. Understanding the impact of anti-cancer agents on the vascular endothelium will inform therapeutic approaches to prevent or reverse treatment-induced cardiotoxicity and may serve as an important tool to predict, monitor, and prevent adverse cardiovascular outcomes in patients undergoing treatment.
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Affiliation(s)
- Janée D Terwoord
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States of America; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America.
| | - Andreas M Beyer
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States of America; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, United States of America
| | - David D Gutterman
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States of America; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America
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25
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Traylor MK, Bauman AJ, Saiyasit N, Frizell CA, Hill BD, Nelson AR, Keller JL. An examination of the relationship among plasma brain derived neurotropic factor, peripheral vascular function, and body composition with cognition in midlife African Americans/Black individuals. Front Aging Neurosci 2022; 14:980561. [PMID: 36092801 PMCID: PMC9453229 DOI: 10.3389/fnagi.2022.980561] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 08/08/2022] [Indexed: 11/22/2022] Open
Abstract
African American/Black individuals have been excluded from several lines of prominent neuroscience research, despite exhibiting disproportionately higher risk factors associated with the onset and magnitude of neurodegeneration. Therefore, the objective of the current investigation was to examine potential relationships among brain derived neurotropic factor (BDNF), peripheral vascular function, and body composition with cognition in a sample of midlife, African American/Black individuals. Midlife adults (men: n = 3, 60 ± 4 years; women: n = 9, 58 ± 5 years) were invited to complete two baseline visits separated by 4 weeks. Peripheral vascular function was determined by venous occlusion plethysmography, a dual-energy X-ray absorptiometry was used to determine body composition, and plasma was collected to quantify BDNF levels. The CNS Vital Signs computer-based test was used to provide scores on numerous cognitive domains. The principal results included that complex attention (r = 0.629) and processing speed (r = 0.734) were significantly (p < 0.05) related to the plasma BDNF values. However, there was no significant (p > 0.05) relationship between any vascular measure and any cognitive domain or BDNF value. Secondary findings included the relationship between lean mass and peak hyperemia (r = 0.758) as well as total hyperemia (r = 0.855). The major conclusion derived from these results was that there is rationale for future clinical trials to use interventions targeting increasing BDNF to potentially improve cognition. Additionally, these results strongly suggest that clinicians aiming to improve cognitive health via improvements in the known risk factor of vascular function should consider interventions capable of promoting the size and function of skeletal muscle, especially in the African American/Black population.
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Affiliation(s)
- Miranda K. Traylor
- Integrative Laboratory of Exercise and Applied Physiology (iLEAP), Department of Health, Kinesiology, and Sport, College of Education and Professional Studies, University of South Alabama, Mobile, AL, United States
| | - Allison J. Bauman
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Napatsorn Saiyasit
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Carl A. Frizell
- Physician Assistant Sciences Program, School of Graduate Studies and Research, Meharry Medical College, Nashville, TN, United States
| | - Benjamin D. Hill
- Department of Psychology, College of Arts and Sciences, University of South Alabama, Mobile, AL, United States
| | - Amy R. Nelson
- Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL, United States
| | - Joshua L. Keller
- Integrative Laboratory of Exercise and Applied Physiology (iLEAP), Department of Health, Kinesiology, and Sport, College of Education and Professional Studies, University of South Alabama, Mobile, AL, United States
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26
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Clayton ZS, Craighead DH, Darvish S, Coppock M, Ludwig KR, Brunt VE, Seals DR, Rossman MJ. Promoting healthy cardiovascular aging: emerging topics. THE JOURNAL OF CARDIOVASCULAR AGING 2022; 2:43. [PMID: 36337728 PMCID: PMC9632540 DOI: 10.20517/jca.2022.27] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The development of age-related cardiovascular (CV) dysfunction increases the risk of CV disease as well as other chronic age-associated disorders, including chronic kidney disease, and Alzheimer's disease and related dementias. Major manifestations of age-associated CV dysfunction that increase disease risk are vascular dysfunction, primarily vascular endothelial dysfunction and arterial stiffening, and elevated systolic blood pressure. Declines in nitric oxide bioavailability secondary to increased oxidative stress and inflammation are established mechanisms of CV dysfunction with aging. Moreover, fundamental mechanisms of aging, termed the "hallmarks of aging" extend to the CV system and, as such, may be considered "hallmarks of CV aging". These mechanisms represent viable therapeutic targets for treating CV dysfunction with aging. Healthy lifestyle behaviors, such as regular aerobic exercise and certain dietary patterns, are considered "first-line" strategies to prevent and/or treat age-associated CV dysfunction. Despite the well-established benefits of these strategies, many older adults do not meet the recommended guidelines for exercise or consume a healthy diet. Therefore, it is important to establish alternative and/or complementary evidence-based approaches to prevent or reverse age-related CV dysfunction. Targeting fundamental mechanisms of CV aging with interventions such as time-efficient exercise training, food-derived molecules, termed nutraceuticals, or select synthetic pharmacological agents represents a promising approach. In the present review, we will highlight emerging topics in the field of healthy CV aging with a specific focus on how exercise, nutrition/dietary patterns, nutraceuticals and select synthetic pharmacological compounds may promote healthy CV aging, in part, by targeting the hallmarks of CV aging.
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Affiliation(s)
- Zachary S Clayton
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Daniel H Craighead
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Sanna Darvish
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - McKinley Coppock
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Katelyn R Ludwig
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Vienna E Brunt
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Douglas R Seals
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Matthew J Rossman
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO 80309, USA
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27
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Saenz-Medina J, Muñoz M, Rodriguez C, Contreras C, Sánchez A, Coronado MJ, Ramil E, Santos M, Carballido J, Prieto D. Hyperoxaluria Induces Endothelial Dysfunction in Preglomerular Arteries: Involvement of Oxidative Stress. Cells 2022; 11:cells11152306. [PMID: 35954150 PMCID: PMC9367519 DOI: 10.3390/cells11152306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/15/2022] [Accepted: 07/24/2022] [Indexed: 02/01/2023] Open
Abstract
Urolithiasis is a worldwide problem and a risk factor for kidney injury. Oxidative stress-associated renal endothelial dysfunction secondary to urolithiasis could be a key pathogenic factor, similar to obesity and diabetes-related nephropathy. The aim of the present study was to characterize urolithiasis-related endothelial dysfunction in a hyperoxaluria rat model of renal lithiasis. Experimental approach: Endothelial dysfunction was assessed in preglomerular arteries isolated from control rats and in which 0.75% ethylene glycol was administered in drinking water. Renal interlobar arteries were mounted in microvascular myographs for functional studies; superoxide generation was measured by chemiluminescence and mRNA and protein expression by RT-PCR and immunofluorescence, respectively. Selective inhibitors were used to study the influence of the different ROS sources, xanthine oxidase, COX-2, Nox1, Nox2 and Nox4. Inflammatory vascular response was also studied by measuring the RNAm expression of NF-κB, MCP-1 and TNFα by RT-PCR. Results: Endothelium-dependent vasodilator responses were impaired in the preglomerular arteries of the hyperoxaluric group along with higher superoxide generation in the renal cortex and vascular inflammation developed by MCP-1 and promoted by NF-κB. The xanthine oxidase inhibitor allopurinol restored the endothelial relaxations and returned superoxide generation to basal values. Nox1 and Nox2 mRNA were up-regulated in arteries from the hyperoxaluric group, and Nox1 and Nox2 selective inhibitors also restored the impaired vasodilator responses and normalized NADPH oxidase-dependent higher superoxide values of renal cortex from the hyperoxaluric group. Conclusions: The current data support that hyperoxaluria induces oxidative stress-mediated endothelial dysfunction and inflammatory response in renal preglomerular arteries which is promoted by the xanthine oxidase, Nox1 and Nox2 pathways.
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Affiliation(s)
- Javier Saenz-Medina
- Department of Urology, Puerta de Hierro-Majadahonda University Hospital, 28222 Majadahonda, Spain;
- Department of Medical Specialties and Public Health, King Juan Carlos University, 28933 Madrid, Spain
- Correspondence: (J.S.-M.); (D.P.)
| | - Mercedes Muñoz
- Department of Physiology, Pharmacy Faculty, Complutense University, 28040 Madrid, Spain; (M.M.); (C.R.); (C.C.); (A.S.)
| | - Claudia Rodriguez
- Department of Physiology, Pharmacy Faculty, Complutense University, 28040 Madrid, Spain; (M.M.); (C.R.); (C.C.); (A.S.)
| | - Cristina Contreras
- Department of Physiology, Pharmacy Faculty, Complutense University, 28040 Madrid, Spain; (M.M.); (C.R.); (C.C.); (A.S.)
| | - Ana Sánchez
- Department of Physiology, Pharmacy Faculty, Complutense University, 28040 Madrid, Spain; (M.M.); (C.R.); (C.C.); (A.S.)
| | - María José Coronado
- Confocal Microscopy Facility, Puerta de Hierro-Majadahonda Research Institute, 28222 Majadahonda, Spain;
| | - Elvira Ramil
- Molecular Biology and DNA Sequencing Facility, Puerta de Hierro-Majadahonda Research Institute, 28222 Majadahonda, Spain;
| | - Martin Santos
- Medical and Surgical Research Facility, Puerta de Hierro-Majadahonda Research Institute, 28222 Majadahonda, Spain;
| | - Joaquín Carballido
- Department of Urology, Puerta de Hierro-Majadahonda University Hospital, 28222 Majadahonda, Spain;
| | - Dolores Prieto
- Department of Medical Specialties and Public Health, King Juan Carlos University, 28933 Madrid, Spain
- Correspondence: (J.S.-M.); (D.P.)
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28
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Ya J, Kadir RRA, Bayraktutan U. Delay of endothelial cell senescence protects cerebral barrier against age-related dysfunction: role of senolytics and senomorphics. Tissue Barriers 2022:2103353. [PMID: 35880392 PMCID: PMC10364655 DOI: 10.1080/21688370.2022.2103353] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022] Open
Abstract
Accumulation of senescent cells in cerebrovasculature is thought to play an important role in age-related disruption of blood-brain barrier (BBB). Using an in vitro model of human BBB, composed of brain microvascular endothelial cells (BMECs), astrocytes and pericytes, this study explored the so-called correlative link between BMEC senescence and the BBB dysfunction in the absence or presence of functionally distinct senotherapeutics. Replicative senescence was deemed present at passage ≥19 where BMECs displayed shortened telomere length, reduced proliferative and tubulogenic potentials and increased NADPH oxidase activity, superoxide anion production (markers of oxidative stress), S-β-galactosidase activity and γ-H2AX staining. Significant impairments observed in integrity and function of a model of BBB established with senescent BMECs, ascertained successively by decreases in transendothelial electrical resistance and increases in paracellular flux, revealed a close correlation between endothelial cell senescence and BBB dysfunction. Disruptions in the localization or expression of tight junction proteins, zonula occludens-1, occludin, and claudin-5 in senescent BMECs somewhat explained this dysfunction. Indeed, treatment of relatively old BMEC (passage 16) with a cocktail of senolytics (dasatinib and quercetin) or senomorphics targeting transcription factor NF-κB (QNZ), p38MAPK signaling pathway (BIRB-796) or pro-oxidant enzyme NADPH oxidase (VAS2870) until passage 20 rendered these cells more resistant to senescence and totally preserved BBB characteristics by restoring subcellular localization and expression of tight junction proteins. In conclusion, attempts that effectively mitigate accumulation of senescent endothelial cells in cerebrovasculature may prevent age-related BBB dysfunction and may be of prophylactic or therapeutic value to extend lifelong health and wellbeing.
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Affiliation(s)
- Jingyuan Ya
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK
| | - Rais Reskiawan A Kadir
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK
| | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK
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Del Cuore A, Pacinella G, Riolo R, Tuttolomondo A. The Role of Immunosenescence in Cerebral Small Vessel Disease: A Review. Int J Mol Sci 2022; 23:ijms23137136. [PMID: 35806140 PMCID: PMC9266569 DOI: 10.3390/ijms23137136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/20/2022] [Accepted: 06/24/2022] [Indexed: 11/16/2022] Open
Abstract
Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an “inflammaging” condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD). The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively. Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.
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Affiliation(s)
- Alessandro Del Cuore
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialised Medicine (PROMISE) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy; (G.P.); (R.R.); (A.T.)
- Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
- Correspondence: ; Tel.: +39-091-655-2197
| | - Gaetano Pacinella
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialised Medicine (PROMISE) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy; (G.P.); (R.R.); (A.T.)
- Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Renata Riolo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialised Medicine (PROMISE) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy; (G.P.); (R.R.); (A.T.)
- Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialised Medicine (PROMISE) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy; (G.P.); (R.R.); (A.T.)
- Internal Medicine and Stroke Care Ward, Policlinico “P. Giaccone”, 90127 Palermo, Italy
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30
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Hsa_circ_0087352 promotes the inflammatory response of macrophages in abdominal aortic aneurysm by adsorbing hsa-miR-149-5p. Int Immunopharmacol 2022; 107:108691. [DOI: 10.1016/j.intimp.2022.108691] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/21/2022] [Accepted: 03/07/2022] [Indexed: 12/18/2022]
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Santamaria-Juarez C, Atonal-Flores F, Diaz A, Sarmiento-Ortega VE, Garcia-Gonzalez M, Aguilar-Alonso P, Lopez-Lopez G, Brambila E, Treviño S. Aortic dysfunction by chronic cadmium exposure is linked to multiple metabolic risk factors that converge in anion superoxide production. Arch Physiol Biochem 2022; 128:748-756. [PMID: 32067514 DOI: 10.1080/13813455.2020.1726403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
CONTEXT The chronic exposure to Cadmium (Cd) constitute an risk to develop hypertension and cardiovascular diseases associated with the increase of oxidative stress. OBJECTIVE In this study, we investigate the role of metabolic changes produced by exposure to Cd on the endothelial dysfunction via oxidative stress. METHODS Male Wistar rats were exposed to Cd (32.5-ppm) for 2-months. The zoometry and blood pressure were evaluated, also glucose and lipids profiles in serum and vascular reactivity evaluated in isolated aorta rings. RESULTS Rats exposed to Cd showed an increase of blood pressure and biochemical parameters similar to metabolic syndrome. Additionally, rats exposed to Cd showed a reduced relaxation in aortic rings, which was reversed after the addition of SOD and apocynin an inhibitor of NADPH. CONCLUSION The Cd-exposition induced hypertension and endothelial injury by that modifying the vascular relaxation and develop oxidative stress via NADPH oxidase, superoxide and loss nitric oxide bioavailability.
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Affiliation(s)
- Celeste Santamaria-Juarez
- Department of Pharmacy, Faculty of Chemistry Science, University Autonomous of Puebla, Puebla, Mexico
| | - Fausto Atonal-Flores
- Department of Physiology, Faculty of Medicine, University Autonomous of Puebla, The Volcano, Mexico
| | - Alfonso Diaz
- Department of Pharmacy, Faculty of Chemistry Science, University Autonomous of Puebla, Puebla, Mexico
| | - Victor E Sarmiento-Ortega
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, University Autonomous of Puebla, Puebla, Mexico
| | - Miguel Garcia-Gonzalez
- Department of Pharmacy, Faculty of Chemistry Science, University Autonomous of Puebla, Puebla, Mexico
| | - Patricia Aguilar-Alonso
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, University Autonomous of Puebla, Puebla, Mexico
| | - Gustavo Lopez-Lopez
- Department of Pharmacy, Faculty of Chemistry Science, University Autonomous of Puebla, Puebla, Mexico
| | - Eduardo Brambila
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, University Autonomous of Puebla, Puebla, Mexico
| | - Samuel Treviño
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, University Autonomous of Puebla, Puebla, Mexico
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Greaney JL, Saunders EFH, Alexander LM. Short-term salicylate treatment improves microvascular endothelium-dependent dilation in young adults with major depressive disorder. Am J Physiol Heart Circ Physiol 2022; 322:H880-H889. [PMID: 35363580 PMCID: PMC9018008 DOI: 10.1152/ajpheart.00643.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 11/22/2022]
Abstract
Reactive oxygen species (ROS)-mediated reductions in nitric oxide (NO)-dependent dilation are evident in adults with major depressive disorder (MDD); however, the upstream mechanisms remain unclear. Here, we hypothesized that nuclear factor-κB (NF-κB) activation-induced ROS production contributes to microvascular endothelial dysfunction in MDD. Thirteen treatment-naive adults with MDD (6 women; 19-23 yr) and 10 healthy nondepressed adults (HAs; 5 women; 20-25 yr) were tested before and after (open-label design) systemic NF-κB knockdown (nonacetylated salicylate; 3,000-4,500 mg/day × 4 days). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh), alone and in combination with NO synthase inhibition [NG-nitro-l-arginine methyl ester (l-NAME)] or ROS scavenging (apocynin). Serum salicylate concentrations following treatment were not different between groups (22.8 ± 7.4 HAs vs. 20.8 ± 4.3 mg/dL MDD; P = 0.46). When compared with HAs, the NO-dependent component of ACh-induced dilation was blunted in adults with MDD before (P = 0.023), but not after (P = 0.27), salsalate treatment. In adults with MDD, the magnitude of improvement in endothelium-dependent dilation following salsalate treatment was inversely related to the degree of functional impairment at baseline (R2 = 0.43; P = 0.025). Localized ROS scavenging improved NO-dependent dilation before (P < 0.01), but not after (P > 0.05), salsalate treatment. Salsalate did not alter systemic concentrations of pro- or anti-inflammatory cytokines (all P > 0.05). These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults with MDD but otherwise free of clinical disease. These data provide the first direct evidence for a mechanistic role of vascular inflammation-associated endothelial dysfunction in human depression.NEW & NOTEWORTHY Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated endothelium-dependent dilation in adults with major depressive disorder (MDD). In adults with MDD, acute localized scavenging of reactive oxygen species (ROS) with apocynin improved NO-dependent dilation before, but not after, salsalate administration. These data suggest that activation of NF-κB, in part via stimulation of vascular ROS production, contributes to blunted NO-mediated endothelium-dependent dilation in young adults with MDD.
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Affiliation(s)
- Jody L Greaney
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania
- Department of Kinesiology, The University of Texas at Arlington, Arlington, Texas
| | - Erika F H Saunders
- Department of Psychiatry and Behavior Health, Penn State College of Medicine, Hershey, Pennsylvania
| | - Lacy M Alexander
- Noll Laboratory, Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania
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Yi X, Zhu QX, Wu XL, Tan TT, Jiang XJ. Histone Methylation and Oxidative Stress in Cardiovascular Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6023710. [PMID: 35340204 PMCID: PMC8942669 DOI: 10.1155/2022/6023710] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/17/2022] [Accepted: 03/05/2022] [Indexed: 11/18/2022]
Abstract
Oxidative stress occurs when ROS overproduction overwhelms the elimination ability of antioxidants. Accumulated studies have found that oxidative stress is regulated by histone methylation and plays a critical role in the development and progression of cardiovascular diseases. Targeting the underlying molecular mechanism to alter the interplay of oxidative stress and histone methylation may enable creative and effective therapeutic strategies to be developed against a variety of cardiovascular disorders. Recently, some drugs targeting epigenetic modifiers have been used to treat specific types of cancers. However, the comprehensive signaling pathways bridging oxidative stress and histone methylation need to be deeply explored in the contexts of cardiovascular physiology and pathology before clinical therapies be developed. In the present review, we summarize and update information on the interplay between histone methylation and oxidative stress during the development of cardiovascular diseases such as atherosclerosis, coronary artery disease, pulmonary hypertension, and diabetic macro- and microvascular pathologies.
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Affiliation(s)
- Xin Yi
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Qiu-Xia Zhu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Xing-Liang Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Tuan-Tuan Tan
- Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xue-Jun Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan 430060, China
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34
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Gupta V, Garg A, Tomar R, Arora MK. Oxidative Stress: Meeting Multiple Targets in Pathogenesis of Vascular Endothelial Dysfunction. Curr Drug Targets 2022; 23:902-912. [PMID: 35240954 DOI: 10.2174/1389450123666220303090413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/20/2021] [Accepted: 12/31/2021] [Indexed: 11/22/2022]
Abstract
Vascular endothelium is the innermost lining of blood vessels, which maintains vasoconstriction and vasodilation. Loss of vascular tone is a hallmark for cardiovascular disorders. Though there are numerous factors, such as over activation of renin angiotensin aldosterone system, kinases, growth factors, etc. play crucial role in induction and progression of vascular abrasion. Interestingly, dysregulation of these pathways either enhances the intensity of oxidative stress, or these pathways are affected by oxidative stress. Thus, oxidative stress has been considered a key culprit in the progression of vascular endothelial dysfunction. Oxidative stress induced by reactive oxygen and nitrogen species causes abnormal gene expression, alteration in signal transduction, and the activation of pathways leading to induction and progression of vascular injury. In addition, numerous antioxidants have been noted to possess promising therapeutic potential in preventing the development of vascular endothelial dysfunction. Therefore, we have focused on current perspectives in oxidative stress signalling to evaluate common biological processes whereby oxidative stress plays a crucial role in the progression of vascular endothelial dysfunction.
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Affiliation(s)
- Vardan Gupta
- Department of Pharmacology, KIET School of Pharmacy, Ghaziabad-250005, Uttar Pradesh, India
| | - Anchal Garg
- Department of Pharmacology, KIET School of Pharmacy, Ghaziabad-250005, Uttar Pradesh, India
| | - Ritu Tomar
- School of Pharmaceutical and Population Health Informatics, DIT University, Dehradun-248009, Uttarakhand, India
| | - Mandeep Kumar Arora
- School of Pharmaceutical and Population Health Informatics, DIT University, Dehradun-248009, Uttarakhand, India
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Stanhewicz AE, Dillon GA, Serviente C, Alexander LM. Acute systemic inhibition of inflammation augments endothelium-dependent dilation in women with a history of preeclamptic pregnancy. Pregnancy Hypertens 2022; 27:81-86. [PMID: 34973597 PMCID: PMC8858855 DOI: 10.1016/j.preghy.2021.12.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/27/2022]
Abstract
Women who have had preeclampsia demonstrate microvascular endothelial-dysfunction, mediated in part by reduced nitric oxide (NO)-dependent dilation. Preeclamptic pregnancies are associated with elevated inflammation, and inhibition of inflammation attenuates endothelial damage in animal models of preeclampsia. However, it is unclear if inhibition of vascular inflammation improves endothelial function in women after a preeclamptic pregnancy. Using the cutaneous microcirculation as a model, we hypothesized that acute systemic inhibition of vascular inflammation (oral salsalate; 1500 mg/twice daily, 4 days) would improve endothelium- and NO-dependent vasodilation in women with a history of preeclampsia (PE) but not in women with a history of uncomplicated pregnancy (HC). Twelve HC (30 ± 1yrs, 10 ± 2 months postpartum) and 10 PE (30 ± 2yrs, 8 ± 2 months postpartum) participated in a double-blind placebo-controlled study. Following each treatment, 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusion of acetylcholine (Ach, 10-7-102mM) or Ach + 15 mM L-NAME (NO synthase antagonist). Red blood cell flux was measured over each site by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28 mM SNP + local heat 43 °C). ACh-induced (77 ± 3 vs. 92 ± 3%CVCmax; p = 0.01) and NO-dependent (20 ± 6 vs. 33 ± 4%; p = 0.02) vasodilation were attenuated in PE compared to HC. Salsalate augmented ACh-induced (95 ± 2%CVCmax; p = 0.002) and NO-dependent (39 ± 3%; p = 0.009) dilation in PE compared to placebo but had no effect in HC (all p > 0.05). Salsalate treatment augmented endothelium-dependent vasodilation via NO-mediated pathways in women who have had preeclampsia, suggesting that inflammatory signaling mediates persistent endothelial dysfunction following preeclampsia.
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Affiliation(s)
- Anna E. Stanhewicz
- Department of Health and Human Physiology, University of Iowa, Iowa City, IA,Department of Kinesiology, Pennsylvania State University, University Park, PA
| | - Gabrielle A. Dillon
- Department of Kinesiology, Pennsylvania State University, University Park, PA,Center for Healthy Aging, Pennsylvania State University, University Park, PA
| | - Corinna Serviente
- Center for Healthy Aging, Pennsylvania State University, University Park, PA,Institute for Applied Life Sciences, University of Massachusetts Amherst, Amherst, MA,Department of Kinesiology, University of Massachusetts Amherst, Amherst, MA
| | - Lacy M. Alexander
- Department of Kinesiology, Pennsylvania State University, University Park, PA,Center for Healthy Aging, Pennsylvania State University, University Park, PA
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Habeeb E, Aldosari S, Saghir SA, Cheema M, Momenah T, Husain K, Omidi Y, Rizvi SA, Akram M, Ansari RA. Role of Environmental Toxicants in the Development of Hypertensive and Cardiovascular Diseases. Toxicol Rep 2022; 9:521-533. [PMID: 35371924 PMCID: PMC8971584 DOI: 10.1016/j.toxrep.2022.03.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
The incidence of hypertension with diabetes mellitus (DM) as a co-morbid condition is on the rise worldwide. In 2000, an estimated 972 million adults had hypertension, which is predicted to grow to 1.56 billion by 2025. Hypertension often leads to diabetes mellitus that strongly puts the patients at an increased risk of cardiovascular, kidney, and/or atherosclerotic diseases. Hypertension has been identified as a major risk factor for the development of diabetes; patients with hypertension are at two-to-three-fold higher risk of developing diabetes than patients with normal blood pressure (BP). Causes for the increase in hypertension and diabetes are not well understood, environmental factors (e.g., exposure to environmental toxicants like heavy metals, organic solvents, pesticides, alcohol, and urban lifestyle) have been postulated as one of the reasons contributing to hypertension and cardiovascular diseases (CVD). The mechanism of action(s) of these toxicants in developing hypertension and CVDs is not well defined. Research studies have linked hypertension with the chronic consumption of alcohol and exposure to metals like lead, mercury, and arsenic have also been linked to hypertension and CVD. Workers chronically exposed to styrene have a higher incidence of CVD. Recent studies have demonstrated that exposure to particulate matter (PM) in diesel exhaust and urban air contributes to increased CVD and mortality. In this review, we have imparted the role of environmental toxicants such as heavy metals, organic pollutants, PM, alcohol, and some drugs in hypertension and CVD along with possible mechanisms and limitations in extrapolating animal data to humans.
Rising incidence of hypertension may be linked to chronic exposure with environmental toxicants. Urban lifestyle and alcohol intake may be responsible for increased incidence of hypertension among urbanites. Exposure with organic solvent, heavy metals and pesticides could also be contributing to the rise in blood pressure.
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Affiliation(s)
- Ehsan Habeeb
- Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200S University Drive, Fort Lauderdale, FL 33200, USA
| | - Saad Aldosari
- Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200S University Drive, Fort Lauderdale, FL 33200, USA
| | - Shakil A. Saghir
- The Scotts Company LLC, Marysville, OH 43041, USA
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
| | - Mariam Cheema
- Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200S University Drive, Fort Lauderdale, FL 33200, USA
| | - Tahani Momenah
- Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200S University Drive, Fort Lauderdale, FL 33200, USA
| | - Kazim Husain
- Department of Gastrointestinal Oncology (FOB-2), Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Yadollah Omidi
- Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200S University Drive, Fort Lauderdale, FL 33200, USA
| | - Syed A.A. Rizvi
- Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, VA 23668, USA
| | - Muhammad Akram
- Department of Eastern Medicine and Surgery, Government College University Faisalabad, Faisalabad, Pakistan
| | - Rais A. Ansari
- Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200S University Drive, Fort Lauderdale, FL 33200, USA
- Corresponding author.
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Association between rs20456 and rs6930913 of Kinesin-Like Family 6 and Hypertension in a Chinese Cohort. Int J Hypertens 2021; 2021:1061800. [PMID: 34961832 PMCID: PMC8710155 DOI: 10.1155/2021/1061800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 11/23/2021] [Accepted: 12/08/2021] [Indexed: 11/17/2022] Open
Abstract
This study aimed to investigate the relationship between kinesin-like family 6 (KIF6) polymorphisms and hypertension in a northeast Chinese cohort. In this study, two single nucleotide polymorphisms of KIF6 (rs20456 and rs6930913) and their haplotype were analyzed in 382 hypertension patients and 378 controls with SHEsis analysis platform, and the gene-environmental interactions were evaluated with logistic regression analysis. After adjusting for confounding factors, significantly lower risk of hypertension was observed in participants with genotype TC (0.416 (CI 0.299–0.578), p < 0.001) and CC (0.577 (0.389–0.857), p=0.007) of rs20456 compared with TT. For rs6930913, allele T (0.522 (0.386–0.704), p < 0.001), genotype TT (0.325 (0.205–0.515), p < 0.001), and genotype CT (0.513 (0.379–0.693), p < 0.001) were significantly associated with lower risk of hypertension than allele C and CC genotype, respectively. Gene-environment analyses confirmed the significant influence on hypertension by the interactions between genotypes distribution in rs20456 (CT: p=0.036, TT: p=0.022) and smoking status. No interactions were found between smoking and rs6930913, except those with dominant or recessive genetic models (both Ps=0.006). There were no interactions between KIF6 and overweight (all Ps > 0.05). Haplotype analyses showed that CC (p=0.005) and TC (p=0.001) of rs20456 and rs6930913 were significantly associated with a statistically increased risk of hypertension. The false-positive report probability (FPRP) analysis was used to verify significant findings. In conclusions, KIF6 might affect the susceptibility of hypertension. The allele C (rs20456) and allele T (rs690913) were inclined to protect individuals from hypertension both in genotype and haplotype analyses.
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Lefferts EC, Hibner BA, Lefferts WK, Lima NS, Baynard T, Haus JM, Lane‐Cordova AD, Phillips SA, Fernhall B. Oral vitamin C restores endothelial function during acute inflammation in young and older adults. Physiol Rep 2021; 9:e15104. [PMID: 34762777 PMCID: PMC8582295 DOI: 10.14814/phy2.15104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 10/14/2021] [Indexed: 11/24/2022] Open
Abstract
Oxidative stress has been linked to reductions in vascular function during acute inflammation in young adults; however, the effect of acute inflammation on vascular function with aging is inconclusive. The aim of this study was to determine if oral antioxidant administration eliminates vascular dysfunction during acute inflammation in young and older adults. Brachial flow-mediated dilation (FMD) and carotid-femoral pulse wave velocity (PWV) were measured in nine young (3 male, 24 ± 4 yrs, 26.2 ± 4.9 kg/m2 ) and 16 older (13 male, 64 ± 5 yrs, 25.8 ± 3.2 kg/m2 ) adults before and 2-h after oral consumption of 2 g of vitamin C. The vitamin C protocol was completed at rest and 24 h after acute inflammation was induced via the typhoid vaccine. Venous blood samples were taken to measure markers of inflammation and vitamin C. Both interleukin-6 (Δ+0.7 ± 1.8 pg/ml) and C-reactive protein (Δ+1.9 ± 3.1 mg/L) were increased at 24 h following the vaccine (p < 0.01). There was no change in FMD or PWV following vitamin C administration at rest (p > 0.05). FMD was lower in all groups during acute inflammation (Δ-1.4 ± 1.9%, p < 0.01), with no changes in PWV (Δ-0.0 ± 0.9 m/s, p > 0.05). Vitamin C restored FMD back to initial values in young and older adults during acute inflammation (Δ+1.0 ± 1.8%, p < 0.01) with no change in inflammatory markers or PWV (p > 0.05). In conclusion, oral vitamin C restored endothelial function during acute inflammation in young and older adults, with no effect on aortic stiffness. The effect of vitamin C on endothelial function did not appear to be due to reductions in inflammatory markers. The exact mechanisms should be further investigated.
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Affiliation(s)
- Elizabeth C. Lefferts
- Department of Kinesiology and NutritionUniversity of Illinois at ChicagoChicagoIllinoisUSA
- Department of KinesiologyIowa State UniversityAmesIowaUSA
| | - Brooks A. Hibner
- Department of Kinesiology and NutritionUniversity of Illinois at ChicagoChicagoIllinoisUSA
| | - Wesley K. Lefferts
- Department of Kinesiology and NutritionUniversity of Illinois at ChicagoChicagoIllinoisUSA
- Department of KinesiologyIowa State UniversityAmesIowaUSA
| | - Natalia S. Lima
- Department of Kinesiology and NutritionUniversity of Illinois at ChicagoChicagoIllinoisUSA
| | - Tracy Baynard
- Department of Kinesiology and NutritionUniversity of Illinois at ChicagoChicagoIllinoisUSA
| | - Jacob M. Haus
- School of KinesiologyUniversity of MichiganAnn ArborMichiganUSA
| | - Abbi D. Lane‐Cordova
- Department of Exercise ScienceArnold School of Public HealthUniversity of South CarolinaColumbiaSouth CarolinaUSA
| | - Shane A. Phillips
- Department of Physical TherapyUniversity of Illinois at ChicagoChicagoIllinoisUSA
| | - Bo Fernhall
- Department of Kinesiology and NutritionUniversity of Illinois at ChicagoChicagoIllinoisUSA
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Espinoza C, Fuenzalida B, Leiva A. Increased Fetal Cardiovascular Disease Risk: Potential Synergy Between Gestational Diabetes Mellitus and Maternal Hypercholesterolemia. Curr Vasc Pharmacol 2021; 19:601-623. [PMID: 33902412 DOI: 10.2174/1570161119666210423085407] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/27/2021] [Accepted: 03/16/2021] [Indexed: 01/25/2023]
Abstract
Cardiovascular diseases (CVD) remain a major cause of death worldwide. Evidence suggests that the risk for CVD can increase at the fetal stages due to maternal metabolic diseases, such as gestational diabetes mellitus (GDM) and maternal supraphysiological hypercholesterolemia (MSPH). GDM is a hyperglycemic, inflammatory, and insulin-resistant state that increases plasma levels of free fatty acids and triglycerides, impairs endothelial vascular tone regulation, and due to the increased nutrient transport, exposes the fetus to the altered metabolic conditions of the mother. MSPH involves increased levels of cholesterol (mainly as low-density lipoprotein cholesterol) which also causes endothelial dysfunction and alters nutrient transport to the fetus. Despite that an association has already been established between MSPH and increased CVD risk, however, little is known about the cellular processes underlying this relationship. Our knowledge is further obscured when the simultaneous presentation of MSPH and GDM takes place. In this context, GDM and MSPH may substantially increase fetal CVD risk due to synergistic impairment of placental nutrient transport and endothelial dysfunction. More studies on the separate and/or cumulative role of both processes are warranted to suggest specific treatment options.
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Affiliation(s)
- Cristian Espinoza
- Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago 8330024, Chile
| | - Barbara Fuenzalida
- Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland
| | - Andrea Leiva
- School of Medical Technology, Health Sciences Faculty, Universidad San Sebastian, Providencia 7510157, Chile
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Ranadive SM, Dillon GA, Mascone SE, Alexander LM. Vascular Health Triad in Humans With Hypertension-Not the Usual Suspects. Front Physiol 2021; 12:746278. [PMID: 34658930 PMCID: PMC8517241 DOI: 10.3389/fphys.2021.746278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/25/2021] [Indexed: 11/13/2022] Open
Abstract
Hypertension (HTN) affects more than one-third of the US population and remains the top risk factor for the development of cardiovascular disease (CVD). Identifying the underlying mechanisms for developing HTN are of critical importance because the risk of developing CVD doubles with ∼20 mmHg increase in systolic blood pressure (BP). Endothelial dysfunction, especially in the resistance arteries, is the primary site for initiation of sub-clinical HTN. Furthermore, inflammation and reactive oxygen and nitrogen species (ROS/RNS) not only influence the endothelium independently, but also have a synergistic influence on each other. Together, the interplay between inflammation, ROS and vascular dysfunction is referred to as the vascular health triad, and affects BP regulation in humans. While the interplay of the vascular health triad is well established, new underlying mechanistic targets are under investigation, including: Inducible nitric oxide synthase, hydrogen peroxide, hydrogen sulfide, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor activated T cells. This review outlines the role of these unusual suspects in vascular health and function in humans. This review connects the dots using these unusual suspects underlying inflammation, ROS and vascular dysfunction especially in individuals at risk of or with diagnosed HTN based on novel studies performed in humans.
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Affiliation(s)
- Sushant M Ranadive
- Department of Kinesiology, University of Maryland, College Park, College Park, MD, United States
| | - Gabrielle A Dillon
- Department of Kinesiology, The Pennsylvania State University, University Park, PA, United States.,Center for Healthy Aging, The Pennsylvania State University, University Park, PA, United States
| | - Sara E Mascone
- Department of Kinesiology, University of Maryland, College Park, College Park, MD, United States
| | - Lacy M Alexander
- Department of Kinesiology, The Pennsylvania State University, University Park, PA, United States.,Center for Healthy Aging, The Pennsylvania State University, University Park, PA, United States
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Kozakova M, Palombo C. Vascular Ageing and Aerobic Exercise. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:10666. [PMID: 34682413 PMCID: PMC8535583 DOI: 10.3390/ijerph182010666] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 12/15/2022]
Abstract
Impairment of vascular function, in particular endothelial dysfunction and large elastic artery stiffening, represents a major link between ageing and cardiovascular risk. Clinical and experimental studies identified numerous mechanisms responsible for age-related decline of endothelial function and arterial compliance. Since most of these mechanisms are related to oxidative stress or low-grade inflammation, strategies that suppress oxidative stress and inflammation could be effective for preventing age-related changes in arterial function. Indeed, aerobic physical activity, which has been shown to improve intracellular redox balance and mitochondrial health and reduce levels of systemic inflammatory markers, also improves endothelial function and arterial distensibility and reduces risk of cardiovascular diseases. The present paper provides a brief overview of processes underlying age-related changes in arterial function, as well as the mechanisms through which aerobic exercise might prevent or interrupt these processes, and thus attenuate vascular ageing.
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Affiliation(s)
- Michaela Kozakova
- Department of Clinical and Experimental Medicine, University of Pisa, 56124 Pisa, Italy;
| | - Carlo Palombo
- Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, 56124 Pisa, Italy
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Moreno-Gómez-Toledano R, Sánchez-Esteban S, Cook A, Mínguez-Moratinos M, Ramírez-Carracedo R, Reventún P, Delgado-Marín M, Bosch RJ, Saura M. Bisphenol A Induces Accelerated Cell Aging in Murine Endothelium. Biomolecules 2021; 11:biom11101429. [PMID: 34680063 PMCID: PMC8533150 DOI: 10.3390/biom11101429] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/21/2021] [Accepted: 09/26/2021] [Indexed: 01/10/2023] Open
Abstract
Bisphenol A (BPA) is a widespread endocrine disruptor affecting many organs and systems. Previous work in our laboratory demonstrated that BPA could induce death due to necroptosis in murine aortic endothelial cells (MAECs). This work aims to evaluate the possible involvement of BPA-induced senescence mechanisms in endothelial cells. The β-Gal assays showed interesting differences in cell senescence at relatively low doses (100 nM and 5 µM). Western blots confirmed that proteins involved in senescence mechanisms, p16 and p21, were overexpressed in the presence of BPA. In addition, the UPR (unfolding protein response) system, which is part of the senescent phenotype, was also explored by Western blot and qPCR, confirming the involvement of the PERK-ATF4-CHOP pathway (related to pathological processes). The endothelium of mice treated with BPA showed an evident increase in the expression of the proteins p16, p21, and CHOP, confirming the results observed in cells. Our results demonstrate that oxidative stress induced by BPA leads to UPR activation and senescence since pretreatment with N-acetylcysteine (NAC) in BPA-treated cells reduced the percentage of senescent cells prevented the overexpression of proteins related to BPA-induced senescence and reduced the activation of the UPR system. The results suggest that BPA participates actively in accelerated cell aging mechanisms, affecting the vascular endothelium and promoting cardiovascular diseases.
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Affiliation(s)
- Rafael Moreno-Gómez-Toledano
- Universidad de Alcalá, Systems Biology Department, IRYCIS, 28772 Alcalá de Henares, Spain; (R.M.-G.-T.); (S.S.-E.); (A.C.); (M.M.-M.); (P.R.); (M.D.-M.); (R.J.B.)
| | - Sandra Sánchez-Esteban
- Universidad de Alcalá, Systems Biology Department, IRYCIS, 28772 Alcalá de Henares, Spain; (R.M.-G.-T.); (S.S.-E.); (A.C.); (M.M.-M.); (P.R.); (M.D.-M.); (R.J.B.)
| | - Alberto Cook
- Universidad de Alcalá, Systems Biology Department, IRYCIS, 28772 Alcalá de Henares, Spain; (R.M.-G.-T.); (S.S.-E.); (A.C.); (M.M.-M.); (P.R.); (M.D.-M.); (R.J.B.)
| | - Marta Mínguez-Moratinos
- Universidad de Alcalá, Systems Biology Department, IRYCIS, 28772 Alcalá de Henares, Spain; (R.M.-G.-T.); (S.S.-E.); (A.C.); (M.M.-M.); (P.R.); (M.D.-M.); (R.J.B.)
| | | | - Paula Reventún
- Universidad de Alcalá, Systems Biology Department, IRYCIS, 28772 Alcalá de Henares, Spain; (R.M.-G.-T.); (S.S.-E.); (A.C.); (M.M.-M.); (P.R.); (M.D.-M.); (R.J.B.)
| | - María Delgado-Marín
- Universidad de Alcalá, Systems Biology Department, IRYCIS, 28772 Alcalá de Henares, Spain; (R.M.-G.-T.); (S.S.-E.); (A.C.); (M.M.-M.); (P.R.); (M.D.-M.); (R.J.B.)
| | - Ricardo J. Bosch
- Universidad de Alcalá, Systems Biology Department, IRYCIS, 28772 Alcalá de Henares, Spain; (R.M.-G.-T.); (S.S.-E.); (A.C.); (M.M.-M.); (P.R.); (M.D.-M.); (R.J.B.)
| | - Marta Saura
- Universidad de Alcalá, Systems Biology Department, IRYCIS, 28772 Alcalá de Henares, Spain; (R.M.-G.-T.); (S.S.-E.); (A.C.); (M.M.-M.); (P.R.); (M.D.-M.); (R.J.B.)
- Correspondence:
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Jeong SJ, Park JG, Oh GT. Peroxiredoxins as Potential Targets for Cardiovascular Disease. Antioxidants (Basel) 2021; 10:antiox10081244. [PMID: 34439492 PMCID: PMC8389283 DOI: 10.3390/antiox10081244] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 07/30/2021] [Indexed: 01/10/2023] Open
Abstract
Increased oxidative stress (OS) is considered a common etiology in the pathogenesis of cardiovascular disease (CVD). Therefore, the precise regulation of reactive oxygen species (ROS) in cardiovascular cells is essential to maintain normal physiological functions. Numerous regulators of cellular homeostasis are reportedly influenced by ROS. Hydrogen peroxide (H2O2), as an endogenous ROS in aerobic cells, is a toxic substance that can induce OS. However, many studies conducted over the past two decades have provided substantial evidence that H2O2 acts as a diffusible intracellular signaling messenger. Antioxidant enzymes, including superoxide dismutases, catalase, glutathione peroxidases, and peroxiredoxins (Prdxs), maintain the balance of ROS levels against augmentation of ROS production during the pathogenesis of CVD. Especially, Prdxs are regulatory sensors of transduced intracellular signals. The intracellular abundance of Prdxs that specifically react with H2O2 act as regulatory proteins. In this review, we focus on the role of Prdxs in the regulation of ROS-induced pathological changes in the development of CVD.
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Affiliation(s)
- Se-Jin Jeong
- Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA;
| | - Jong-Gil Park
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea
- Correspondence: (J.-G.P.); (G.T.O.); Tel.: +82-42-860-4122 (J.-G.P.); +82-2-3277-4128 (G.T.O.); Fax: +82-42-860-4149 (J.-G.P.); +82-2-3277-3760 (G.T.O.)
| | - Goo Taeg Oh
- Department of Life Sciences, Heart-Immune-Brain Network Research Center, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Korea
- Correspondence: (J.-G.P.); (G.T.O.); Tel.: +82-42-860-4122 (J.-G.P.); +82-2-3277-4128 (G.T.O.); Fax: +82-42-860-4149 (J.-G.P.); +82-2-3277-3760 (G.T.O.)
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Trott DW, Machin DR, Phuong TTT, Adeyemo AO, Bloom SI, Bramwell RC, Sorensen ES, Lesniewski LA, Donato AJ. T cells mediate cell non-autonomous arterial ageing in mice. J Physiol 2021; 599:3973-3991. [PMID: 34164826 PMCID: PMC8425389 DOI: 10.1113/jp281698] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/21/2021] [Indexed: 11/08/2022] Open
Abstract
KEY POINTS Increased large artery stiffness and impaired endothelium-dependent dilatation occur with advanced age. We sought to determine whether T cells mechanistically contribute to age-related arterial dysfunction. We found that old mice exhibited greater proinflammatory T cell accumulation around both the aorta and mesenteric arteries. Pharmacologic depletion or genetic deletion of T cells in old mice resulted in ameliorated large artery stiffness and greater endothelium-dependent dilatation compared with mice with T cells intact. ABSTRACT Ageing of the arteries is characterized by increased large artery stiffness and impaired endothelium-dependent dilatation. T cells contribute to hypertension in acute rodent models but whether they contribute to chronic age-related arterial dysfunction is unknown. To determine whether T cells directly mediate age-related arterial dysfunction, we examined large elastic artery and resistance artery function in young (4-6 months) and old (22-24 months) wild-type mice treated with anti-CD3 F(ab'2) fragments to deplete T cells (150 μg, i.p. every 7 days for 28 days) or isotype control fragments. Old mice exhibited greater numbers of T cells in both aorta and mesenteric vasculature when compared with young mice. Old mice treated with anti-CD3 fragments exhibited depletion of T cells in blood, spleen, aorta and mesenteric vasculature. Old mice also exhibited greater numbers of aortic and mesenteric IFN-γ and TNF-α-producing T cells when compared with young mice. Old control mice exhibited greater large artery stiffness and impaired resistance artery endothelium-dependent dilatation in comparison with young mice. In old mice, large artery stiffness was ameliorated with anti-CD3 treatment. Anti-CD3-treated old mice also exhibited greater endothelium-dependent dilatation than age-matched controls. We also examined arterial function in young and old Rag-1-/- mice, which lack lymphocytes. Rag-1-/- mice exhibited blunted increases in large artery stiffness with age compared with wild-type mice. Old Rag-1-/- mice also exhibited greater endothelium-dependent dilatation compared with old wild-type mice. Collectively, these results demonstrate that T cells play an important role in age-related arterial dysfunction.
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Affiliation(s)
- Daniel W Trott
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
- Department of Kinesiology, University of Texas at Arlington, Texas, USA
| | - Daniel R Machin
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Tam T T Phuong
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - AdeLola O Adeyemo
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Samuel I Bloom
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, USA
| | - R Colton Bramwell
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Eric S Sorensen
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Lisa A Lesniewski
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, USA
- Geriatrics Research Education and Clinical Center, Veteran's Affairs Medical Center, Salt Lake City, Utah, USA
| | - Anthony J Donato
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, USA
- Geriatrics Research Education and Clinical Center, Veteran's Affairs Medical Center, Salt Lake City, Utah, USA
- Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA
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Tuttolomondo A, Del Cuore A, La Malfa A, Casuccio A, Daidone M, Maida CD, Di Raimondo D, Di Chiara T, Puleo MG, Norrito R, Guercio G, Pinto A. Assessment of heart rate variability (HRV) in subjects with type 2 diabetes mellitus with and without diabetic foot: correlations with endothelial dysfunction indices and markers of adipo-inflammatory dysfunction. Cardiovasc Diabetol 2021; 20:142. [PMID: 34261479 PMCID: PMC8281716 DOI: 10.1186/s12933-021-01337-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/05/2021] [Indexed: 11/10/2022] Open
Abstract
Background Some studies have suggested that patients with diabetes and foot complications have worse cardiovascular and cerebrovascular risk profiles, higher degrees of endothelial dysfunction and arterial stiffness and a higher inflammatory background than patients with diabetes without diabetic foot complications. Patients with diabetes mellitus have an alteration in the sympathovagal balance as assessed by means of heart rate variability (HRV) analysis, which is also related to the presence of endothelial dysfunction. Other studies suggest a possible role of inflammation coexisting with the alteration in the sympathovagal balance in favor of the atherosclerotic process in a mixed population of healthy subjects of middle and advanced age. Aims The aim of this study was to evaluate the degree of alteration of sympathovagal balance, assessed by HRV analysis, in a cohort of patients with diabetes mellitus with diabetic foot and in control subjects without diabetic foot compared with a population of healthy subjects and the possible correlation of HRV parameters with inflammatory markers and endothelial dysfunction indices. Methods We enrolled all patients with diabetic ulcerative lesions of the lower limb in the Internal Medicine with Stroke Care ward and of the diabetic foot outpatient clinic of P. Giaccone University Hospital of Palermo between September 2019 and July 2020. 4-h ECG Holter was performed. The following time domain HRV measures were analyzed: average heart rate, square root of the mean of successive differences of NN (RMSSD), standard deviation or square root of the variance (SD), and standard deviation of the means of the NN intervals calculated over a five-minute period (SDANN/5 min). The LF/HF ratio was calculated, reactive hyperemia was evaluated by endo-PAT, and serum levels of vaspine and omentin-1 were assessed by blood sample collection. Results 63 patients with diabetic foot, 30 patients with diabetes and without ulcerative complications and 30 patients without diabetes were enrolled. Patients with diabetic ulcers showed lower mean diastolic blood pressure values than healthy controls, lower MMSE scores corrected for age, lower serum levels of omentin-1, lower RHI values, higher body weight values and comparable body height values, HF% and LF/HF ratio values. We also reported a negative correlation between the RHI value and HRV indices and the expression of increased parasympathetic activity (RMSDD and HF%) in subjects with diabetic foot and a statistically significant positive correlation with the LF/HF ratio and the expression of the sympathovagal balance. Discussion Patients with diabetic foot show a higher degree of activation of the parasympathetic system, expressed by the increase in HF values, and a lower LF/HF ratio. Our findings may corroborate the issue that a parasympathetic dysfunction may have a possible additive role in the pathogenesis of other vascular complications in subjects with diabetic foot.
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Affiliation(s)
- Antonino Tuttolomondo
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy. .,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy.
| | - Alessandro Del Cuore
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Alessandro La Malfa
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Alessandra Casuccio
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Mario Daidone
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Carlo Domenico Maida
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Domenico Di Raimondo
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Tiziana Di Chiara
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Maria Grazia Puleo
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Rosario Norrito
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
| | - Giovanni Guercio
- Department of Surgical Oncological and Stomatological Disciplines, University of Palermo, Palermo, Italy
| | - Antonio Pinto
- Internal Medicine and Stroke Care Ward, University of Palermo, Palermo, Italy.,Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), University of Palermo, Palermo, Italy
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Brunt VE, Casso AG, Gioscia-Ryan RA, Sapinsley ZJ, Ziemba BP, Clayton ZS, Bazzoni AE, VanDongen NS, Richey JJ, Hutton DA, Zigler MC, Neilson AP, Davy KP, Seals DR. Gut Microbiome-Derived Metabolite Trimethylamine N-Oxide Induces Aortic Stiffening and Increases Systolic Blood Pressure With Aging in Mice and Humans. Hypertension 2021; 78:499-511. [PMID: 33966451 DOI: 10.1161/hypertensionaha.120.16895] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Vienna E Brunt
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Abigail G Casso
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Rachel A Gioscia-Ryan
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Zachary J Sapinsley
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Brian P Ziemba
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Zachary S Clayton
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Amy E Bazzoni
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Nicholas S VanDongen
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - James J Richey
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - David A Hutton
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Melanie C Zigler
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
| | - Andrew P Neilson
- Department of Food Science and Technology (A.P.N.).,Now with Department of Food, Bioprocessing and Nutrition Sciences, North Carolina State University, Kannapolis (A.P.N.)
| | - Kevin P Davy
- Department of Human Nutrition, Foods, and Exercise (K.P.D.), Virginia Tech, Blacksburg
| | - Douglas R Seals
- From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., A.G.C., R.A.G.-R., Z.J.S., B.P.Z., Z.S.C., A.E.B., N.S.V., J.J.R., D.A.H., M.C.Z., D.R.S.)
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Shen T, Wang J, Yang W, Li L, Qiao Y, Yan X, Chen M, Tang X, Zou J, Zhao Y. Hematological Parameters Characteristics in Children with Obstructive Sleep Apnea with Obesity. Risk Manag Healthc Policy 2021; 14:1015-1023. [PMID: 33737842 PMCID: PMC7961133 DOI: 10.2147/rmhp.s297341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/24/2021] [Indexed: 02/05/2023] Open
Abstract
Objective To investigate the possible correlation between obesity and hematological parameters in children with obstructive sleep apnea (OSA). Methods A total of 460 children was initially included in our study, which were divided into children with OSA and children without OSA. Multiple analysis was performed for obesity by adjusting confounding factors such as age and gender in 460 children. Further, to minimize the influence of confounding factors and selective bias, propensity score matching (PSM) was performed in children with OSA. Hematological parameters such as inflammatory and coagulable parameters were compared between the normal weight children with OSA and the obese children with OSA following PSM. Results OSA (OR = 3.061; P<0.001; 95% CI, 1.772–5.288) represented an independent risk factor for obesity. Besides, the obese children with OSA had higher levels of white blood cell (WBC) (P<0.001), neutrophil (NEUT) (P<0.001), neutrophil-lymphocyte ratio (NLR) (P=0.006), fibrinogen (FIB) (P=0.033), while had a lower level of activated partial thromboplastin time (APTT) (P=0.048). No significant differences were observed in other hematological parameters. In linear regression, the results indicated that the levels of WBC (R2 = 0.123, Beta = 0.289, P<0.001), NEUT (R2 = 0.124, Beta = 0.282, P<0.001), NLR (R2 = 0.105, Beta = 0.184, P=0.026) and FIB (R2 = 0.086, Beta = 0.246, P=0.003) were positively correlated with BMI, while the level of APTT (R2 = 0.057, Beta = −0.171, P=0.044) was significantly negatively correlated with BMI. Conclusion OSA was an independent risk factor contributing to obesity. WBC, NEUT, NLR, FIB and APTT are correlated with obesity in children with OSA (aged from 2 to 14 years). These indicators could be used to estimate the status of inflammation and hypercoagulation in the obese children with OSA.
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Affiliation(s)
- Tian Shen
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jing Wang
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Wen Yang
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Linke Li
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yixin Qiao
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Xiaohong Yan
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Min Chen
- Department of Otorhinolaryngology Head and Neck Surgery, Chengdu Shangjin Nanfu Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Xiangdong Tang
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jian Zou
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Yu Zhao
- Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
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Izzo C, Vitillo P, Di Pietro P, Visco V, Strianese A, Virtuoso N, Ciccarelli M, Galasso G, Carrizzo A, Vecchione C. The Role of Oxidative Stress in Cardiovascular Aging and Cardiovascular Diseases. Life (Basel) 2021; 11:60. [PMID: 33467601 PMCID: PMC7829951 DOI: 10.3390/life11010060] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Aging can be seen as process characterized by accumulation of oxidative stress induced damage. Oxidative stress derives from different endogenous and exogenous processes, all of which ultimately lead to progressive loss in tissue and organ structure and functions. The oxidative stress theory of aging expresses itself in age-related diseases. Aging is in fact a primary risk factor for many diseases and in particular for cardiovascular diseases and its derived morbidity and mortality. Here we highlight the role of oxidative stress in age-related cardiovascular aging and diseases. We take into consideration the molecular mechanisms, the structural and functional alterations, and the diseases accompanied to the cardiovascular aging process.
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Affiliation(s)
- Carmine Izzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
| | - Paolo Vitillo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
| | - Paola Di Pietro
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
| | - Valeria Visco
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
| | - Andrea Strianese
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
| | - Nicola Virtuoso
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
| | - Gennaro Galasso
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
| | - Albino Carrizzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
- Department of Angio-Cardio-Neurology, Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Isernia, Italy
| | - Carmine Vecchione
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; (C.I.); (P.V.); (P.D.P.); (V.V.); (A.S.); (N.V.); (M.C.); (G.G.); (A.C.)
- Department of Angio-Cardio-Neurology, Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Isernia, Italy
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49
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Jian B, Hu M, Cai W, Zhang B, Lu Z. Update of Immunosenescence in Cerebral Small Vessel Disease. Front Immunol 2020; 11:585655. [PMID: 33362768 PMCID: PMC7756147 DOI: 10.3389/fimmu.2020.585655] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/16/2020] [Indexed: 12/31/2022] Open
Abstract
Aging of the central nervous system (CNS) is closely associated with chronic sterile low-grade inflammation in older organisms and related immune response. As an amplifier for neuro-inflammaging, immunosenescence remodels and deteriorates immune systems gradually with the passage of time, and finally contributes to severe outcomes like stroke, dementia and neurodegeneration in elderly adults. Cerebral small vessel disease (CSVD), one of the major causes of vascular dementia, has an intensive connection with the inflammatory response and immunosenescence plays a crucial role in the pathology of this disorder. In this review, we discuss the impact of immunosenescence on the development of CSVD and its underlying mechanism. Furthermore, the clinical practice significance of immunosenescence management and the diagnosis and treatment of CSVD will be also discussed.
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Affiliation(s)
- Banghao Jian
- Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mengyan Hu
- Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wei Cai
- Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Center of Clinical Immunology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bingjun Zhang
- Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhengqi Lu
- Department of Neurology, Center for Mental and Neurological Disorders and Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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50
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Jiang F, Xu XR, Li WM, Xia K, Wang LF, Yang XC. Monotropein alleviates H2O2‑induced inflammation, oxidative stress and apoptosis via NF‑κB/AP‑1 signaling. Mol Med Rep 2020; 22:4828-4836. [PMID: 33173962 PMCID: PMC7646929 DOI: 10.3892/mmr.2020.11548] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Aging is a major risk factor in cardiovascular disease (CVD). Oxidative stress and inflammation are involved in the pathogenesis of CVD, and are closely associated with senescent vascular endothelial cells. Monotropein (Mtp) exerts various bioactive roles, including anti‑inflammatory and antioxidative effects. The aim of the present study was to investigate the function of Mtp in senescent endothelial cells. An MTT assay was performed to evaluate the influence of Mtp on H2O2‑stimulated human umbilical vein endothelial cells (HUVECs). Senescent cells were assessed by determining the expression of senescence‑associated β‑galactosidase, high mobility group AT‑hook 1 and DNA damage marker γ‑H2A.X variant histone. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH‑Px) and proinflammatory cytokine concentrations were estimated using assay kits to evaluate the levels of oxidative stress and inflammation in HUVECs. The TUNEL assay was performed to identify apoptotic cells. Furthermore, the expression levels of endothelial cell adhesion factors, NF‑κB, activator protein‑1 (AP‑1) and apoptotic proteins were determined via western blotting. Mtp enhanced HUVEC viability following H2O2 stimulation. H2O2‑mediated increases in MDA, proinflammatory cytokine and endothelial cell adhesion factor levels were decreased by Mtp treatment, whereas Mtp reversed H2O2‑mediated downregulation of SOD and GSH‑Px activity. Furthermore, Mtp inhibited cell apoptosis, NF‑κB activation and AP‑1 expression in H2O2‑stimulated HUVECs; however, NF‑κB activator counteracted the anti‑inflammatory, antioxidative and antiapoptotic effects of Mtp. The present study indicated that Mtp ameliorated H2O2‑induced inflammation and oxidative stress potentially by regulating NF‑κB/AP‑1.
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Affiliation(s)
- Feng Jiang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Xiao-Rong Xu
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Wei-Ming Li
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Kun Xia
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Le-Feng Wang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Xin-Chun Yang
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R. China
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