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Zhang YY, Li YJ, Hu XQ, Xue CD, Li S, Gao ZN, Qin KR. Unveiling the Negative Synergistic Effect of Wall Shear Stress and Insulin on Endothelial NO Dynamics by Mathematical Modeling. Bull Math Biol 2025; 87:46. [PMID: 39969626 DOI: 10.1007/s11538-025-01424-2] [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: 08/29/2024] [Accepted: 02/03/2025] [Indexed: 02/20/2025]
Abstract
Diabetic vascular complications (DVCs) are diabetes-induced vascular dysfunction and pathologies, leading to the major causes of morbidity and mortality in millions of diabetic patients worldwide. DVCs are provoked by endothelial dysfunction which is closely coordinated with two important hallmarks: one is the insufficient insulin secretion or insulin resistance, and another is the decrease in intracellular nitric oxide (NO) influenced by dynamic wall shear stress (WSS). Although the intracellular NO dynamics in endothelial cells (ECs) is crucial for endothelial function, the regulation of NO production by dynamic WSS and insulin is still poorly understood. In this study, we have proposed a mathematical model of intracellular NO production in ECs under the stimulation of dynamic WSS combined with insulin. The model integrates simultaneously the biochemical signaling pathways of insulin and the mechanotransduction pathways induced by dynamic WSS. The accuracy and reliability of the model to quantitatively describe NO production in ECs were compared and validated with reported experimental data. According to the validated model, inhibition of protein kinase B (AKT) phosphorylation and Ca2+ influx by dynamic oscillatory WSS disrupts the dual nature of endothelial nitric oxide synthase (eNOS) enzyme activation. This disruption leads to the decrease in NO production and the bimodal disappearance of NO waveforms. Moreover, the results reveal that dynamic WSS combined with insulin promote endothelial NO production through negative synergistic effects, which is resulted from the temporal differences in mechanical and biochemical signaling. In brief, the proposed model elucidates the mechanism of NO generation activated by dynamic WSS combined with insulin, providing a potential target and theoretical framework for future treatment of DVCs.
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Affiliation(s)
- Yu-Yuan Zhang
- Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, 116024, Liaoning, People's Republic of China
| | - Yong-Jiang Li
- Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China.
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, 116024, Liaoning, People's Republic of China.
| | - Xu-Qu Hu
- Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, 116024, Liaoning, People's Republic of China
| | - Chun-Dong Xue
- Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, 116024, Liaoning, People's Republic of China
| | - Shen Li
- Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China
| | - Zheng-Nan Gao
- Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China
| | - Kai-Rong Qin
- Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116033, Liaoning, People's Republic of China.
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, 116024, Liaoning, People's Republic of China.
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Burma JS, Virk S, Smirl JD. Systolic versus diastolic differences in cerebrovascular reactivity to hypercapnic and hypocapnic challenges. Eur J Appl Physiol 2025; 125:429-442. [PMID: 39305369 DOI: 10.1007/s00421-024-05621-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 09/18/2024] [Indexed: 02/16/2025]
Abstract
INTRODUCTION Cerebrovascular reactivity (CVR) describes the vasculature's response to vasoactive stimuli, where prior investigations relied solely on mean data, rather than exploring cardiac cycle differences. METHODS Seventy-one participants (46 females and 25 males) from two locations underwent TCD measurements within the middle or posterior cerebral arteries (MCA, PCA). Females were tested in the early-follicular phase. The hypercapnia response was assessed using a rebreathing protocol (93% oxygen and 7% carbon dioxide) or dynamic end-tidal forcing as a cerebral blood velocity (CBv) change from 40 to 55-Torr. The hypocapnia response was quantified using a hyperventilation protocol as a CBv change from 40 to 25-Torr. Absolute and relative CVR slopes were compared across cardiac cycle phases, vessels, and biological sexes using analysis of covariance with Tukey post-hoc comparisons. RESULTS No differences were found between hypercapnia methods used (p > 0.050). Absolute hypercapnic slopes were highest in systole (p < 0.001), with no cardiac cycle differences for absolute hypocapnia (p > 0.050). Relative slopes were largest in diastole and smallest in systole for both hypercapnia and hypocapnia (p < 0.001). Females exhibited greater absolute CVR responses (p < 0.050), while only the relative systolic hypercapnic response was different between sexes (p = 0.001). Absolute differences were present between the MCA and PCA (p < 0.001), which vanished when normalizing data to baseline values (p > 0.050). CONCLUSION Cardiac cycle variations impact CVR responses, with females displaying greater absolute CVR in some cardiac phases during the follicular window. These findings are likely due to sex differences in endothelial receptors/signalling pathways. Future CVR studies should employ assessments across the cardiac cycle.
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Affiliation(s)
- Joel S Burma
- Cerebrovascular Concussion Lab, Faculty of Kinesiology, University of Calgary, Alberta, Canada.
- Sport Injury Prevention Research Centre, Faculty of Kinesiology, Department of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada.
- Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.
- Libin Cardiovascular Institute of Alberta, University of Calgary, Alberta, Canada.
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
| | - Saroor Virk
- Cerebrovascular Concussion Lab, Faculty of Kinesiology, University of Calgary, Alberta, Canada
| | - Jonathan D Smirl
- Cerebrovascular Concussion Lab, Faculty of Kinesiology, University of Calgary, Alberta, Canada
- Sport Injury Prevention Research Centre, Faculty of Kinesiology, Department of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB, T2N 1N4, Canada
- Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada
- Libin Cardiovascular Institute of Alberta, University of Calgary, Alberta, Canada
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
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Gonzalez M, Clayton S, Wauson E, Christian D, Tran QK. Promotion of nitric oxide production: mechanisms, strategies, and possibilities. Front Physiol 2025; 16:1545044. [PMID: 39917079 PMCID: PMC11799299 DOI: 10.3389/fphys.2025.1545044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 01/07/2025] [Indexed: 02/09/2025] Open
Abstract
The discovery of nitric oxide (NO) and the role of endothelial cells (ECs) in its production has revolutionized medicine. NO can be produced by isoforms of NO synthases (NOS), including the neuronal (nNOS), inducible (iNOS), and endothelial isoforms (eNOS), and via the non-classical nitrate-nitrite-NO pathway. In particular, endothelium-derived NO, produced by eNOS, is essential for cardiovascular health. Endothelium-derived NO activates soluble guanylate cyclase (sGC) in vascular smooth muscle cells (VSMCs), elevating cyclic GMP (cGMP), causing vasodilation. Over the past four decades, the importance of this pathway in cardiovascular health has fueled the search for strategies to enhance NO bioavailability and/or preserve the outcomes of NO's actions. Currently approved approaches operate in three directions: 1) providing exogenous NO, 2) promoting sGC activity, and 3) preventing degradation of cGMP by inhibiting phosphodiesterase 5 activity. Despite clear benefits, these approaches face challenges such as the development of nitrate tolerance and endothelial dysfunction. This highlights the need for sustainable options that promote endogenous NO production. This review will focus on strategies to promote endogenous NO production. A detailed review of the mechanisms regulating eNOS activity will be first provided, followed by a review of strategies to promote endogenous NO production based on the levels of available preclinical and clinical evidence, and perspectives on future possibilities.
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Affiliation(s)
| | | | | | | | - Quang-Kim Tran
- Department of Physiology and Pharmacology, Des Moines University Medicine and Health Sciences, West Des Moines, IA, United States
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Yao J, Zhang Y, Wang Z, Chen Y, Shi X. Maintenance of Cardiac Microenvironmental Homeostasis: A Joint Battle of Multiple Cells. J Cell Physiol 2025; 240:e31496. [PMID: 39632594 DOI: 10.1002/jcp.31496] [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: 07/02/2024] [Revised: 10/24/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024]
Abstract
Various cells such as cardiomyocytes, fibroblasts and endothelial cells constitute integral components of cardiac tissue. The health and stability of cardiac ecosystem are ensured by the action of a certain type of cell and the intricate interactions between multiple cell types. The dysfunctional cells exert a profound impact on the development of cardiovascular diseases by involving in the pathological process. In this paper, we introduce the dynamic activity, cell surface markers as well as biological function of the various cells in the heart. Besides, we discuss the multiple signaling pathways involved in the cardiac injury including Hippo/YAP, TGF-β/Smads, PI3K/Akt, and MAPK signaling. The complexity of different cell types poses a great challenge to the disease treatment. By characterizing the roles of various cell types in cardiovascular diseases, we sought to discuss the potential strategies for preventing and treating cardiovascular diseases.
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Affiliation(s)
- Jiayu Yao
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Youtao Zhang
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Ziwen Wang
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Yuejun Chen
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
| | - Xingjuan Shi
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China
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Garcia VP, Stockelman KA, Levy MV, Fandl HK, Goulding A, Hijmans JG, Ruzzene ST, Berry AR, Greiner JJ, DeSouza CA. Microvesicles Derived from Nitric Oxide Synthase-Inhibited Endothelial Cells Promote Cell Dysfunction. J Vasc Res 2024; 62:10-21. [PMID: 39657607 DOI: 10.1159/000542280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 10/22/2024] [Indexed: 12/12/2024] Open
Abstract
INTRODUCTION The aims of this study were to determine (1) whether endothelial nitric oxide synthase (eNOS) inhibition stimulates endothelial microvesicles (EMVs) release and (2) the effect of EMVs derived from eNOS-inhibited cells on endothelial cell eNOS, inflammation, apoptosis, and tissue-type plasminogen activator (t-PA). METHODS Human umbilical vein endothelial cells (HUVECs) were treated with the eNOS inhibitor (NG-nitro-l-arginine methyl ester [L-NAME], 300 µM) for 24 h. EMVs from untreated and L-NAME-treated cells were isolated, quantified, and exposed to HUVECs for 24 h. RESULTS eNOS-inhibited cells released significantly higher EMVs than untreated cells (81 ± 13 vs. 41 ± 15 EMV/μL; p = 0.005). Expression of total eNOS (97.1 ± 16.4 vs. 157.5 ± 31.2 arbitrary units [AUs]; p = 0.01), p-eNOS (4.9 ± 1.2 vs. 9.1 ± 12.6 AUs; p = 0.02), and NO production (5.0 ± 0.8 vs. 7.0 ± 1.3 µmol/L; p = 0.04) were significantly lower in cells treated with EMVs from L-NAME-treated cells. L-NAME-derived EMVs induced significantly higher IL-6 (38.3 ± 10.3 vs. 21.0 ± 3.8 pg/mL; p = 0.01) and IL-8 (38.9 ± 7.0 vs. 27.2 ± 6.2 pg/mL; p = 0.04) production concurrent with higher expression of p-NF-κB p65 (Ser536) (9.7 ± 1.6 vs. 6.1 ± 1.2 AUs; p = 0.01). Expression of activated caspase-3 was higher (9.5 ± 1.1 vs. 6.4 ± 0.4 AUs) and t-PA lower (24.2 ± 4.3 vs. 36.2 ± 8.4 AUs; p = 0.04) in cells treated with L-NAME-derived EMVs. CONCLUSION eNOS inhibition induces an increase in EMV release and an EMV phenotype with adverse cellular effects.
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Affiliation(s)
- Vinicius P Garcia
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Kelly A Stockelman
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Ma'ayan V Levy
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Hannah K Fandl
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Anabel Goulding
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Jamie G Hijmans
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Samuel T Ruzzene
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Auburn R Berry
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Jared J Greiner
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
| | - Christopher A DeSouza
- Integrative Vascular Biology Laboratory, Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA
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Shao Y, Gan Z, Wang T, Shao Z, Yu H, Qin S, Mei H, Chen T, Fu X, Liu G, Chen M. Correlation of the triglyceride-glucose index and heart rate with 28-day all-cause mortality in severely ill patients: analysis of the MIMIC-IV database. Lipids Health Dis 2024; 23:387. [PMID: 39574113 PMCID: PMC11580213 DOI: 10.1186/s12944-024-02358-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 11/03/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Research has identified a link between the triglyceride-glucose index (TyG-i) and the risk of mortality in severely ill patients. However, it remains uncertain if the TyG-i affects mortality by influencing heart rate (HR). METHODS This study enrolled 3,509 severely ill participants from the Medical Information Mart for Intensive Care (MIMIC-IV) database who had triglyceride, glucose, and HR data upon entering the ICU. Cox regression models were applied to estimate the effect of the TyG-i and HR on 28-day all-cause mortality (ACM) and 28-day in-hospital mortality (IHM). Additionally, Kaplan-Meier (K-M) survival analysis was employed to explore outcome variations among different patient groups. The association of the TyG-i with HR, Sequential Organ Failure Assessment (SOFA) score, and Simplified Acute Physiology Score (SAPS) II was explored through linear regression analysis. Subgroup analysis explored potential interactions among patient characteristics, while sensitivity analysis gauged the robustness of the findings. Additionally, mediation analysis was conducted to assess whether elevated HR acts as an intermediary factor linking the TyG-i to both 28-day ACM and 28-day IHM. RESULTS During the 28-day follow-up, 586 cases (16.7%) died from all causes, and 439 cases (12.5%) died during hospitalisation. Cox results showed that individuals with a heightened TyG-i and elevated HR had the highest 28-day ACM (Hazard Ratio 1.70, P-value below 0.001) and 28-day IHM (Hazard Ratio 1.72, P-value below 0.001) compared to those with a reduced TyG-i and HR. The K-M curves showed that individuals with low TyG-i and low HR had the lowest incidence of 28-day ACM and 28-day IHM. The linear analysis results evidenced that the TyG-i was independently connected to HR (beta = 3.05, P-value below 0.001), and the TyG-i was also independently associated with SOFA score (beta = 0.39, P-value below 0.001) and SAPS II (beta = 1.79, P-value below 0.001). Subgroup analysis revealed a significant association in participants without hypertension, the interaction of an elevated TyG-i and HR strongly correlated with a higher 28-day death risk (interaction P-value below 0.05). Furthermore, HR mediated 29.5% of the connection between the TyG-i and 28-day ACM (P-value = 0.002), as well as 20.4% of the connection between the TyG-i and 28-day IHM (P-value = 0.002). CONCLUSION For severely ill patients, the TyG-i is distinctly correlated with HR, and elevated levels of both are strongly connected to greater 28-day ACM and 28-day IHM risks, especially in patients without hypertension. Furthermore, elevated HR mediates the connection between the TyG-i and 28-day mortality.
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Affiliation(s)
- Yuekai Shao
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Zhikun Gan
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Taishan Wang
- Department of Anesthesiology, Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, 551700, China
| | - Zhiqiang Shao
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Hong Yu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Song Qin
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Hong Mei
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Tao Chen
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Xiaoyun Fu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Guoyue Liu
- Intensive Care Unit, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China.
| | - Miao Chen
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China.
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Mierke CT. Mechanosensory entities and functionality of endothelial cells. Front Cell Dev Biol 2024; 12:1446452. [PMID: 39507419 PMCID: PMC11538060 DOI: 10.3389/fcell.2024.1446452] [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] [Received: 06/09/2024] [Accepted: 10/04/2024] [Indexed: 11/08/2024] Open
Abstract
The endothelial cells of the blood circulation are exposed to hemodynamic forces, such as cyclic strain, hydrostatic forces, and shear stress caused by the blood fluid's frictional force. Endothelial cells perceive mechanical forces via mechanosensors and thus elicit physiological reactions such as alterations in vessel width. The mechanosensors considered comprise ion channels, structures linked to the plasma membrane, cytoskeletal spectrin scaffold, mechanoreceptors, and junctional proteins. This review focuses on endothelial mechanosensors and how they alter the vascular functions of endothelial cells. The current state of knowledge on the dysregulation of endothelial mechanosensitivity in disease is briefly presented. The interplay in mechanical perception between endothelial cells and vascular smooth muscle cells is briefly outlined. Finally, future research avenues are highlighted, which are necessary to overcome existing limitations.
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Zhou T, Cheng J, He S, Zhang C, Gao MX, Zhang LJ, Sun JP, Zhu Y, Ai D. The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid. Nat Metab 2024; 6:1566-1583. [PMID: 38907081 DOI: 10.1038/s42255-024-01070-3] [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] [Received: 08/10/2023] [Accepted: 05/23/2024] [Indexed: 06/23/2024]
Abstract
Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or Gq signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34Nter. Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ-S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1-Gq-Ca2+-eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis.
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Affiliation(s)
- Ting Zhou
- State Key Laboratory of Experimental Hematology, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Jie Cheng
- NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, and New Cornerstone Science Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Shuo He
- State Key Laboratory of Experimental Hematology, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Chao Zhang
- NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, and New Cornerstone Science Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Ming-Xin Gao
- NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, and New Cornerstone Science Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Li-Jun Zhang
- NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, and New Cornerstone Science Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Jin-Peng Sun
- NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, and New Cornerstone Science Laboratory, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
| | - Yi Zhu
- State Key Laboratory of Experimental Hematology, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
| | - Ding Ai
- State Key Laboratory of Experimental Hematology, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
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Prajapat SK, Maharana KC, Singh S. Mitochondrial dysfunction in the pathogenesis of endothelial dysfunction. Mol Cell Biochem 2024; 479:1999-2016. [PMID: 37642880 DOI: 10.1007/s11010-023-04835-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 08/14/2023] [Indexed: 08/31/2023]
Abstract
Cardiovascular diseases (CVDs) are a matter of concern worldwide, and mitochondrial dysfunction is one of the major contributing factors. Vascular endothelial dysfunction has a major role in the development of atherosclerosis because of the abnormal chemokine secretion, inflammatory mediators, enhancement of LDL oxidation, cytokine elevation, and smooth muscle cell proliferation. Endothelial cells transfer oxygen from the pulmonary circulatory system to the tissue surrounding the blood vessels, and a majority of oxygen is transferred to the myocardium by endothelial cells, which utilise a small amount of oxygen to generate ATP. Free radicals of oxide are produced by mitochondria, which are responsible for cellular oxygen uptake. Increased mitochondrial ROS generation and reduction in agonist-stimulated eNOS activation and nitric oxide bioavailability were directly linked to the observed change in mitochondrial dynamics, resulting in various CVDs and endothelial dysfunction. Presently, the manuscript mainly focuses on endothelial dysfunction, providing a deep understanding of the various features of mitochondrial mechanisms that are used to modulate endothelial dysfunction. We talk about recent findings and approaches that may make it possible to detect mitochondrial dysfunction as a potential biomarker for risk assessment and diagnosis of endothelial dysfunction. In the end, we cover several targets that may reduce mitochondrial dysfunction through both direct and indirect processes and assess the impact of several different classes of drugs in the context of endothelial dysfunction.
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Affiliation(s)
- Suresh Kumar Prajapat
- National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, Hajipur, Bihar, India
| | - Krushna Ch Maharana
- National Institute of Pharmaceutical Education and Research, Export Promotion Industrial Park (EPIP) Zandaha Road, Hajipur, Bihar, India
| | - Sanjiv Singh
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP), Industrial Area, Dist: Vaishali, Hajipur, Bihar, 844102, India.
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Ren C, Chang Z, Li K, Wang X, Wang D, Xu Y, Li X, Li Q. Impact of uniaxial cyclic stretching on matrix-associated endothelial cell responses. Mater Today Bio 2024; 27:101152. [PMID: 39104901 PMCID: PMC11298614 DOI: 10.1016/j.mtbio.2024.101152] [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: 04/09/2024] [Revised: 06/07/2024] [Accepted: 07/08/2024] [Indexed: 08/07/2024] Open
Abstract
Uniaxial cyclic stretching plays a pivotal role in the fields of tissue engineering and regenerative medicine, influencing cell behaviors and functionality based on physical properties, including matrix morphology and mechanical stimuli. This study delves into the response of endothelial cells to uniaxial cyclic strain within the geometric constraints of micro-nano fibers. Various structural scaffold forms of poly(l-lactide-co-caprolactone) (PLCL), such as flat membranes, randomly oriented fiber membranes, and aligned fiber membranes, were fabricated through solvent casting and electrospinning methods. Our investigation focuses on the morphological variation of endothelial cells under diverse geometric constraints and the mechanical-dependent release of nitric oxide (NO) on oriented fibrous membranes. Our results indicate that while uniaxial cyclic stretching promotes endothelial cell spreading, the anisotropy of the matrix morphology remains the primary driving factor for cell alignment. Additionally, uniaxial cyclic stretching significantly enhances NO release, with a notably stronger effect correlated to the increasing strain amplitude. Importantly, this study reveals that uniaxial cyclic stretching enhances the mRNA expression of key proteins, including talin, vinculin, rac, and nitric oxide synthase (eNOS).
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Affiliation(s)
- Cuihong Ren
- School of Mechanics and Safety Engineering, Zhengzhou University, Zhengzhou, 450001, PR China
- National Center for International Research of Micro-Nano Molding Technology, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Zhonghua Chang
- Institute of Laser Manufacturing, Henan Academy of Sciences, Zhengzhou, 450046, PR China
| | - Kecheng Li
- School of Mechanics and Safety Engineering, Zhengzhou University, Zhengzhou, 450001, PR China
- National Center for International Research of Micro-Nano Molding Technology, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Xiaofeng Wang
- School of Mechanics and Safety Engineering, Zhengzhou University, Zhengzhou, 450001, PR China
- National Center for International Research of Micro-Nano Molding Technology, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Dongfang Wang
- School of Mechanics and Safety Engineering, Zhengzhou University, Zhengzhou, 450001, PR China
- National Center for International Research of Micro-Nano Molding Technology, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Yiyang Xu
- National Center for International Research of Micro-Nano Molding Technology, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Xiaomeng Li
- School of Mechanics and Safety Engineering, Zhengzhou University, Zhengzhou, 450001, PR China
- National Center for International Research of Micro-Nano Molding Technology, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Qian Li
- School of Mechanics and Safety Engineering, Zhengzhou University, Zhengzhou, 450001, PR China
- National Center for International Research of Micro-Nano Molding Technology, Zhengzhou University, Zhengzhou, 450001, PR China
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11
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Edwards JJ, Coleman DA, Ritti-Dias RM, Farah BQ, Stensel DJ, Lucas SJE, Millar PJ, Gordon BDH, Cornelissen V, Smart NA, Carlson DJ, McGowan C, Swaine I, Pescatello LS, Howden R, Bruce-Low S, Farmer CKT, Leeson P, Sharma R, O'Driscoll JM. Isometric Exercise Training and Arterial Hypertension: An Updated Review. Sports Med 2024; 54:1459-1497. [PMID: 38762832 PMCID: PMC11239608 DOI: 10.1007/s40279-024-02036-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2024] [Indexed: 05/20/2024]
Abstract
Hypertension is recognised as a leading attributable risk factor for cardiovascular disease and premature mortality. Global initiatives towards the prevention and treatment of arterial hypertension are centred around non-pharmacological lifestyle modification. Exercise recommendations differ between professional and scientific organisations, but are generally unanimous on the primary role of traditional aerobic and dynamic resistance exercise. In recent years, isometric exercise training (IET) has emerged as an effective novel exercise intervention with consistent evidence of reductions in blood pressure (BP) superior to that reported from traditional guideline-recommended exercise modes. Despite a wealth of emerging new data and endorsement by select governing bodies, IET remains underutilised and is not widely prescribed in clinical practice. This expert-informed review critically examines the role of IET as a potential adjuvant tool in the future clinical management of BP. We explore the efficacy, prescription protocols, evidence quality and certainty, acute cardiovascular stimulus, and physiological mechanisms underpinning its anti-hypertensive effects. We end the review with take-home suggestions regarding the direction of future IET research.
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Affiliation(s)
- Jamie J Edwards
- School of Psychology and Life Sciences, Canterbury Christ Church University, Kent, CT1 1QU, UK
| | - Damian A Coleman
- School of Psychology and Life Sciences, Canterbury Christ Church University, Kent, CT1 1QU, UK
| | - Raphael M Ritti-Dias
- Graduate Program in Rehabilitation Sciences, University Nove de Julho, São Paulo, Brazil
| | - Breno Q Farah
- Department of Physical Education, Universidade Federal Rural de Pernambuco, Recife, Brazil
| | - David J Stensel
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and the University of Leicester, Leicester, UK
- Faculty of Sport Sciences, Waseda University, Tokyo, Japan
- Department of Sports Science and Physical Education, The Chinese University of Hong Kong, Hong Kong, China
| | - Sam J E Lucas
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK
| | - Philip J Millar
- Human Cardiovascular Physiology Laboratory, Department of Human Health and Nutritional Sciences, College of Biological Sciences, University of Guelph, Guelph, ON, Canada
| | - Ben D H Gordon
- Department of Health and Human Development, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Neil A Smart
- School of Science and Technology, University of New England, Armidale, NSW, Australia
| | - Debra J Carlson
- School of Health, Medical and Applied Sciences, CQ University, North Rockhampton, QLD, Australia
| | - Cheri McGowan
- Department of Kinesiology, University of Windsor, Windsor, ON, Canada
| | - Ian Swaine
- Sport Science, University of Greenwich, London, UK
| | - Linda S Pescatello
- Department of Kinesiology, University of Connecticut, Storrs, CT, 06269, USA
| | - Reuben Howden
- Department of Applied Physiology, Health and Clinical Sciences, UNC Charlotte, Charlotte, NC, 28223, USA
| | - Stewart Bruce-Low
- Department of Applied Sport and Exercise Science, University of East London, London, UK
| | | | - Paul Leeson
- Oxford Clinical Cardiovascular Research Facility, Department of Cardiovascular Medicine, University of Oxford, Oxford, UK
| | - Rajan Sharma
- Department of Cardiology, St George's University Hospitals NHS Foundation Trust, Blackshaw Road, Tooting, London, SW17 0QT, UK
| | - Jamie M O'Driscoll
- School of Psychology and Life Sciences, Canterbury Christ Church University, Kent, CT1 1QU, UK.
- Department of Cardiology, St George's University Hospitals NHS Foundation Trust, Blackshaw Road, Tooting, London, SW17 0QT, UK.
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12
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Wang L, Wan W, Zhang S, Keswani T, Li G, Xiao J. RNA-mediated epigenetic regulation in exercised heart: Mechanisms and opportunities for intervention. Mol Aspects Med 2024; 97:101274. [PMID: 38653129 DOI: 10.1016/j.mam.2024.101274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/21/2024] [Accepted: 04/12/2024] [Indexed: 04/25/2024]
Abstract
Physical exercise has been widely acknowledged as a beneficial lifestyle alteration and a potent non-pharmacological treatment for heart disease. Extensive investigations have revealed the beneficial effects of exercise on the heart and the underlying mechanisms involved. Exercise is considered one of the key factors that can lead to epigenetic alterations. The increasing number of identified molecules in the exercised heart has led to many studies in recent years that have explored the cellular function of ncRNAs and RNA modifications in the heart. Investigating the regulatory role of RNA-mediated epigenetic regulation in exercised hearts will contribute to the development of therapeutic strategies for the management of heart diseases. This review aims to summarize the positive impact of exercise on cardiac health. We will first provide an overview of the mechanisms through which exercise offers protection to the heart. Subsequently, we will delve into the current understanding of ncRNAs, specifically miRNAs, lncRNAs, and circRNAs, as well as RNA modification, focusing on RNA m6A and RNA A-to-I editing, and how they contribute to exercise-induced benefits for the heart. Lastly, we will explore the emerging therapeutic strategies that utilize exercise-mediated RNA epigenetic regulation in the treatment of heart diseases, while also addressing the challenges faced in this field.
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Affiliation(s)
- Lijun Wang
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Wensi Wan
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Shuang Zhang
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Tarun Keswani
- Center for Immunological and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA
| | - Guoping Li
- Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Junjie Xiao
- Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), School of Life Science, Shanghai University, Shanghai, 200444, China.
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13
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Van Schoor K, Bruet E, Jones EAV, Migeotte I. Origin and flow-mediated remodeling of the murine and human extraembryonic circulation systems. Front Physiol 2024; 15:1395006. [PMID: 38818524 PMCID: PMC11137303 DOI: 10.3389/fphys.2024.1395006] [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] [Received: 03/02/2024] [Accepted: 04/16/2024] [Indexed: 06/01/2024] Open
Abstract
The transduction of mechanical stimuli produced by blood flow is an important regulator of vascular development. The vitelline and umbilico-placental circulations are extraembryonic vascular systems that are required for proper embryonic development in mammalian embryos. The morphogenesis of the extraembryonic vasculature and the cardiovascular system of the embryo are hemodynamically and molecularly connected. Here we provide an overview of the establishment of the murine and human vitelline and umbilico-placental vascular systems and how blood flow influences various steps in their development. A deeper comprehension of extraembryonic vessel development may aid the establishment of stem-cell based embryo models and provide novel insights to understanding pregnancy complications related to the umbilical cord and placenta.
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Affiliation(s)
- Kristof Van Schoor
- Institut de Recherche Interdisciplinaire Jacques E. Dumont, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Emmanuel Bruet
- Institut de Recherche Interdisciplinaire Jacques E. Dumont, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Elizabeth Anne Vincent Jones
- Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium
- Department of Cardiology CARIM School for Cardiovascular Diseases Maastricht University, Maastricht, Netherlands
| | - Isabelle Migeotte
- Institut de Recherche Interdisciplinaire Jacques E. Dumont, Université Libre de Bruxelles (ULB), Brussels, Belgium
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14
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Dao E, Barha CK, Zou J, Wei N, Liu-Ambrose T. Prevention of Vascular Contributions to Cognitive Impairment and Dementia: The Role of Physical Activity and Exercise. Stroke 2024; 55:812-821. [PMID: 38410973 DOI: 10.1161/strokeaha.123.044173] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/14/2023] [Accepted: 01/03/2024] [Indexed: 02/28/2024]
Abstract
Vascular contributions to cognitive impairment and dementia, specifically cerebral small vessel disease (CSVD), are the second most common cause of dementia. Currently, there are no specific pharmacological treatments for CSVD, and the use of conventional antidementia drugs is not recommended. Exercise has the potential to prevent and mitigate CSVD-related brain damage and improve cognitive function. Mechanistic pathways underlying the neurocognitive benefits of exercise include the control of vascular risk factors, improving endothelial function, and upregulating exerkines. Notably, the therapeutic efficacy of exercise may vary by exercise type (ie, aerobic versus resistance training) and biological sex; thus, studies designed specifically to examine these moderating factors within a CSVD context are needed. Furthermore, future research should prioritize resistance training interventions, given their tremendous therapeutic potential. Addressing these knowledge gaps will help us refine exercise recommendations to maximize their therapeutic impact in the prevention and mitigation of CSVD.
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Affiliation(s)
- Elizabeth Dao
- Department of Radiology (E.D.)
- Department of Physical Therapy, Aging, Mobility, and Cognitive Health Laboratory (E.D., J.Z., N.W., T.L.-A.), Faculty of Medicine, The University of British Columbia, Vancouver, Canada
- Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada (E.D., J.Z., N.W., T.L.-A.)
| | - Cindy K Barha
- Faculty of Kinesiology (C.K.B.), University of Calgary, AB, Canada
- Hotchkiss Brain Institute (C.K.B.), University of Calgary, AB, Canada
| | - Jammy Zou
- Department of Physical Therapy (J.Z., N.W., T.L.-A.)
- Department of Physical Therapy, Aging, Mobility, and Cognitive Health Laboratory (E.D., J.Z., N.W., T.L.-A.), Faculty of Medicine, The University of British Columbia, Vancouver, Canada
- Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada (E.D., J.Z., N.W., T.L.-A.)
- Centre for Aging SMART at Vancouver Coastal Health, Vancouver Coastal Health Research Institute, BC, Canada (J.Z., N.W., T.L.-A.)
| | - Nathan Wei
- Department of Physical Therapy (J.Z., N.W., T.L.-A.)
- Department of Physical Therapy, Aging, Mobility, and Cognitive Health Laboratory (E.D., J.Z., N.W., T.L.-A.), Faculty of Medicine, The University of British Columbia, Vancouver, Canada
- Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada (E.D., J.Z., N.W., T.L.-A.)
- Centre for Aging SMART at Vancouver Coastal Health, Vancouver Coastal Health Research Institute, BC, Canada (J.Z., N.W., T.L.-A.)
| | - Teresa Liu-Ambrose
- Department of Physical Therapy (J.Z., N.W., T.L.-A.)
- Department of Physical Therapy, Aging, Mobility, and Cognitive Health Laboratory (E.D., J.Z., N.W., T.L.-A.), Faculty of Medicine, The University of British Columbia, Vancouver, Canada
- Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, Canada (E.D., J.Z., N.W., T.L.-A.)
- Centre for Aging SMART at Vancouver Coastal Health, Vancouver Coastal Health Research Institute, BC, Canada (J.Z., N.W., T.L.-A.)
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15
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D’Agostino A, Lanzafame LG, Buono L, Crisci G, D’Assante R, Leone I, De Vito L, Bossone E, Cittadini A, Marra AM. Modulating NO-GC Pathway in Pulmonary Arterial Hypertension. Int J Mol Sci 2023; 25:36. [PMID: 38203205 PMCID: PMC10779316 DOI: 10.3390/ijms25010036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/10/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.
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Affiliation(s)
- Anna D’Agostino
- IRCCS SYNLAB SDN, Via Emanuele Gianturco 113, 80143 Naples, Italy; (A.D.); (L.B.); (I.L.)
| | - Lorena Gioia Lanzafame
- Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi Hospital, University of Catania, Via Palermo 636, 95122 Catania, Italy;
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy; (G.C.); (R.D.); (L.D.V.); (A.C.)
| | - Lorena Buono
- IRCCS SYNLAB SDN, Via Emanuele Gianturco 113, 80143 Naples, Italy; (A.D.); (L.B.); (I.L.)
| | - Giulia Crisci
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy; (G.C.); (R.D.); (L.D.V.); (A.C.)
| | - Roberta D’Assante
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy; (G.C.); (R.D.); (L.D.V.); (A.C.)
| | - Ilaria Leone
- IRCCS SYNLAB SDN, Via Emanuele Gianturco 113, 80143 Naples, Italy; (A.D.); (L.B.); (I.L.)
| | - Luigi De Vito
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy; (G.C.); (R.D.); (L.D.V.); (A.C.)
| | - Eduardo Bossone
- Department of Public Health, “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy;
| | - Antonio Cittadini
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy; (G.C.); (R.D.); (L.D.V.); (A.C.)
- Gender Interdipartimental Institute of Research (GENESIS), “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy
| | - Alberto Maria Marra
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy; (G.C.); (R.D.); (L.D.V.); (A.C.)
- Gender Interdipartimental Institute of Research (GENESIS), “Federico II” University of Naples, Via Pansini 5, 80131 Naples, Italy
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16
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Katoh K. Effects of Mechanical Stress on Endothelial Cells In Situ and In Vitro. Int J Mol Sci 2023; 24:16518. [PMID: 38003708 PMCID: PMC10671803 DOI: 10.3390/ijms242216518] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/14/2023] [Accepted: 11/15/2023] [Indexed: 11/26/2023] Open
Abstract
Endothelial cells lining blood vessels are essential for maintaining vascular homeostasis and mediate several pathological and physiological processes. Mechanical stresses generated by blood flow and other biomechanical factors significantly affect endothelial cell activity. Here, we review how mechanical stresses, both in situ and in vitro, affect endothelial cells. We review the basic principles underlying the cellular response to mechanical stresses. We also consider the implications of these findings for understanding the mechanisms of mechanotransducer and mechano-signal transduction systems by cytoskeletal components.
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Affiliation(s)
- Kazuo Katoh
- Laboratory of Human Anatomy and Cell Biology, Faculty of Health Sciences, Tsukuba University of Technology, Tsukuba 305-8521, Japan
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17
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Sala C, Rescaldani M, Gherbesi E, Bolla G, Cuspidi C, Ruscica M, Carugo S. Platelet Cyclic GMP Levels Are Reduced in Patients with Primary Aldosteronism. J Clin Med 2023; 12:7081. [PMID: 38002693 PMCID: PMC10672647 DOI: 10.3390/jcm12227081] [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: 08/29/2023] [Revised: 10/26/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND AND AIM Nitric oxide inhibits platelet aggregation by increasing the second messenger cyclic guanosine-3',5'-monophosphate (cGMP) through the activation of soluble guanylyl cyclase in target cells. Within this context, the oxidative stress associated with the aldosterone excess impairs the nitric oxide availability. Thus, the aim of the present study was to assess the impact of chronic aldosterone excess on the platelet nitric oxide/cGMP pathway in humans. METHODS The levels of cGMP were evaluated in platelets of male patients, 12 with primary aldosteronism (PA) and 32 with uncomplicated essential hypertension (EH), matched for age and blood pressure (BP) values. RESULTS PA and EH patients were 52.8 ± 3 years old and 51.6 ± 1.6 years old, respectively. Systolic and diastolic BP were 158 ± 5.0 mmHg and 105.9 ± 2.3 mmHg in PA and did not differ compared to EH patients (156.6 ± 2.4 mmHg and 104.7 ± 1.2 mmHg). Mean aldosterone levels were significantly higher in PA (25.5 ± 8.8 ng/dL) compared toEH (8.11 ± 0.73 ng/dL), whereas potassium was significantly lower in PA (3.52 ± 0.18 mEq/L) compared to EH (4.08 ± 0.04 mEq/L). Aldosterone and potassium were inversely related (r = -0.49, p = 0.0006) in the whole study population (n = 44). Platelet cGMP was significantly lower in PA (5.1 ± 0.36 pM/109 cells) than in EH (7.1 ± 0.53 pM/109 cells), and in the entire study cohort, it was directly related to plasma potassium (r = 0.43, p = 0.0321). CONCLUSIONS These results show an impairment of nitric oxide/cGMP signaling in platelets of PA patients. This effect is likely related to the potassium-depleting effect of chronic aldosterone excess. Future studies are needed to understand whether the platelet nitric oxide/cGMP system is involved in the atherothrombotic events in these patients.
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Affiliation(s)
- Carla Sala
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Marta Rescaldani
- Cardiovascular Department, Association Socio Sanitary Territorial Santi Paolo e Carlo, 20153 Milan, Italy;
| | - Elisa Gherbesi
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
| | - Gianni Bolla
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Cesare Cuspidi
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy;
| | - Massimiliano Ruscica
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, 20122 Milan, Italy
| | - Stefano Carugo
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
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18
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Roy R, Wilcox J, Webb AJ, O’Gallagher K. Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential. Int J Mol Sci 2023; 24:15200. [PMID: 37894881 PMCID: PMC10607291 DOI: 10.3390/ijms242015200] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics.
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Affiliation(s)
- Roman Roy
- Cardiovascular Department, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
| | - Joshua Wilcox
- Cardiovascular Department, Guy’s and St. Thomas’ NHS Foundation Trust, London SE1 7EH, UK;
| | - Andrew J. Webb
- Department of Clinical Pharmacology, British Heart Foundation Centre, School of Cardiovascular and Metabolic Medicine and Sciences, King’s College London, London SE1 7EH, UK;
| | - Kevin O’Gallagher
- Cardiovascular Department, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK
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19
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Andrabi SM, Sharma NS, Karan A, Shahriar SMS, Cordon B, Ma B, Xie J. Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303259. [PMID: 37632708 PMCID: PMC10602574 DOI: 10.1002/advs.202303259] [Citation(s) in RCA: 156] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Indexed: 08/28/2023]
Abstract
Nitric oxide (NO) is a gaseous molecule that has a central role in signaling pathways involved in numerous physiological processes (e.g., vasodilation, neurotransmission, inflammation, apoptosis, and tumor growth). Due to its gaseous form, NO has a short half-life, and its physiology role is concentration dependent, often restricting its function to a target site. Providing NO from an external source is beneficial in promoting cellular functions and treatment of different pathological conditions. Hence, the multifaceted role of NO in physiology and pathology has garnered massive interest in developing strategies to deliver exogenous NO for the treatment of various regenerative and biomedical complexities. NO-releasing platforms or donors capable of delivering NO in a controlled and sustained manner to target tissues or organs have advanced in the past few decades. This review article discusses in detail the generation of NO via the enzymatic functions of NO synthase as well as from NO donors and the multiple biological and pathological processes that NO modulates. The methods for incorporating of NO donors into diverse biomaterials including physical, chemical, or supramolecular techniques are summarized. Then, these NO-releasing platforms are highlighted in terms of advancing treatment strategies for various medical problems.
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Affiliation(s)
- Syed Muntazir Andrabi
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Navatha Shree Sharma
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Anik Karan
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - S. M. Shatil Shahriar
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Brent Cordon
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Bing Ma
- Cell Therapy Manufacturing FacilityMedStar Georgetown University HospitalWashington, DC2007USA
| | - Jingwei Xie
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
- Department of Mechanical and Materials EngineeringCollege of EngineeringUniversity of Nebraska LincolnLincolnNE68588USA
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20
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Mollace R, Scarano F, Bava I, Carresi C, Maiuolo J, Tavernese A, Gliozzi M, Musolino V, Muscoli S, Palma E, Muscoli C, Salvemini D, Federici M, Macrì R, Mollace V. Modulation of the nitric oxide/cGMP pathway in cardiac contraction and relaxation: Potential role in heart failure treatment. Pharmacol Res 2023; 196:106931. [PMID: 37722519 DOI: 10.1016/j.phrs.2023.106931] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/09/2023] [Accepted: 09/15/2023] [Indexed: 09/20/2023]
Abstract
Evidence exists that heart failure (HF) has an overall impact of 1-2 % in the global population being often associated with comorbidities that contribute to increased disease prevalence, hospitalization, and mortality. Recent advances in pharmacological approaches have significantly improved clinical outcomes for patients with vascular injury and HF. Nevertheless, there remains an unmet need to clarify the crucial role of nitric oxide/cyclic guanosine 3',5'-monophosphate (NO/cGMP) signalling in cardiac contraction and relaxation, to better identify the key mechanisms involved in the pathophysiology of myocardial dysfunction both with reduced (HFrEF) as well as preserved ejection fraction (HFpEF). Indeed, NO signalling plays a crucial role in cardiovascular homeostasis and its dysregulation induces a significant increase in oxidative and nitrosative stress, producing anatomical and physiological cardiac alterations that can lead to heart failure. The present review aims to examine the molecular mechanisms involved in the bioavailability of NO and its modulation of downstream pathways. In particular, we focus on the main therapeutic targets and emphasize the recent evidence of preclinical and clinical studies, describing the different emerging therapeutic strategies developed to counteract NO impaired signalling and cardiovascular disease (CVD) development.
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Affiliation(s)
- Rocco Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Italy
| | - Federica Scarano
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Irene Bava
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Cristina Carresi
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Jessica Maiuolo
- Pharmaceutical Biology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Annamaria Tavernese
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Micaela Gliozzi
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Vincenzo Musolino
- Pharmaceutical Biology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Saverio Muscoli
- Division of Cardiology, Foundation PTV Polyclinic Tor Vergata, Rome 00133, Italy
| | - Ernesto Palma
- Veterinary Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Carolina Muscoli
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
| | - Daniela Salvemini
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Italy
| | - Roberta Macrì
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy.
| | - Vincenzo Mollace
- Pharmacology Laboratory, Institute of Research for Food Safety and Health IRC-FSH, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy; Renato Dulbecco Institute, Lamezia Terme, Catanzaro 88046, Italy.
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21
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Hanson BE, Casey DP. Intermittent versus continuous handgrip exercise and peripheral endothelial function: impact of shear rate fluctuations. J Appl Physiol (1985) 2023; 135:892-901. [PMID: 37650140 DOI: 10.1152/japplphysiol.00362.2023] [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: 06/07/2023] [Revised: 08/08/2023] [Accepted: 08/26/2023] [Indexed: 09/01/2023] Open
Abstract
Sustained exercise-induced elevations in shear rate (SR) have been well established as beneficial for improving endothelial function. However, the impact of intermittent fluctuations in SR is not understood. We investigated the effect of intermittent SR elevations compared with sustained elevations on peripheral endothelial function. Brachial artery flow-mediated dilation (FMD) was assessed in 13 adults (9 M/4 F; 22 ± 4 yr) before and after 30 min of handgrip exercise. Three different rhythmic forearm exercise interventions were performed at a rate of 20 contractions/min. Intermittent exercises (6 × 3 min exercise interspersed by 2 min of rest) were performed at 25% (INT-25%) and 15% (INT-15%) maximum voluntary contraction (MVC), and continuous exercise was completed at 15% MVC. Brachial artery diameter and velocity were measured using Doppler ultrasound. The total increase in SR above baseline throughout exercise was greater during INT-25% (4,441 ± 516 s-1) and continuous (4,070 ± 407 s-1) compared with INT-15% (2,811 ± 342 s-1, P < 0.05). The %FMD increased following all exercises (INT-25%: 5.7 ± 1.2% to 8.1 ± 1.2%; INT-15%: 5.2 ± 1.2% to 7.0 ± 1.1%; continuous: 5.5 ± 1.3% to 6.8 ± 1.3%, P < 0.05 for all). The increase following INT-25% was significantly greater than INT-15% and continuous (P < 0.05 for both). Normalized FMD to shear rate area under the curve increased with intermittent exercise (INT-25%: 2.2 ± 0.2% to 3.4 ± 0.3%; INT-15%: 2.1 ± 0.2% to 3.2 ± 0.2%, P < 0.05 for both) but did not following continuous (2.1 ± 0.2% to 2.5 ± 0.1%, P = 0.06). The increase in normalized FMD with intermittent exercises were greater than continuous (P < 0.05 for both). These findings suggest intermittent fluctuations in SR during handgrip exercise may be more beneficial than sustained elevations on improving peripheral endothelial function.NEW & NOTEWORTHY Exercise-induced increases in shear rate is a well-established stimulus for improving peripheral endothelial function. This study presents novel findings that intermittent elevations in shear rate may be more effective at acutely improving endothelial function compared with continuous elevations. Despite similar increases in total shear rate during handgrip exercise intermittent elevations produced a significantly greater increase in endothelial function when compared with continuous elevations potentially indicating intermittent elevations as a more effective stimulus for acute improvements.
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Affiliation(s)
- Brady E Hanson
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
| | - Darren P Casey
- Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States
- Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa, United States
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, United States
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22
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Chen Q, Chen J, Li J, Cheng Y, Zhang R, Liu Z. Recent advances of oxidative stress in thromboangiitis obliterans: biomolecular mechanisms, biomarkers, sources and clinical applications. Thromb Res 2023; 230:64-73. [PMID: 37639784 DOI: 10.1016/j.thromres.2023.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/29/2023] [Accepted: 08/21/2023] [Indexed: 08/31/2023]
Abstract
Oxidative stress (OS) has been identified as a key factor in the development of Thromboangiitis Obliterans (TAO). The detection of OS levels in clinical and scientific research practice is mainly based on the measurement of oxidative stress such as reactive oxygen species (ROS), reactive nitrogen species (RNS) and lipid peroxides. These markers are typically assessed through a combination of physical and chemical methods. Smoking is known to the state of OS in TAO, and OS levels are significantly increased in smokers due to inadequate antioxidant protection, which leads to the expression of apoptotic proteins and subsequent cell injury, thrombosis and limb ischemia. There, understanding the role of OS in the pathogenesis of TAO may provide insights into the etiology of TAO and a basis for its prevention and treatment.
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Affiliation(s)
- Qi Chen
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Jing Chen
- Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
| | - Jiahua Li
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Yuanyuan Cheng
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Rong Zhang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Zhongqiu Liu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
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23
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Zeng X, Xue CD, Li YJ, Qin KR. A mathematical model for intracellular NO and ROS dynamics in vascular endothelial cells activated by exercise-induced wall shear stress. Math Biosci 2023; 359:109009. [PMID: 37086782 DOI: 10.1016/j.mbs.2023.109009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/17/2023] [Accepted: 04/06/2023] [Indexed: 04/24/2023]
Abstract
Vascular endothelial cells (ECs) residing in the innermost layer of blood vessels are exposed to dynamic wall shear stress (WSS) induced by blood flow. The intracellular nitric oxide (NO) and reactive oxygen species (ROS) in ECs modulated by the dynamic WSS play important roles in endothelial functions. Mathematical modeling is a popular methodology for biophysical studies. It can not only explain existing cell experiments, but also reveal the underlying mechanism. However, the previous mathematical models of NO dynamics in ECs are limited to the static WSS induced by constant flow, while arterial blood flow is a periodic pulsatile flow with varying amplitude and frequency at different exercise intensities. In this study, a mathematical model of intracellular NO and ROS dynamics activated by dynamic WSS based on the in vitro cell experiments is developed. With the hypothesis of the viscoelastic body, the Kelvin model is adopted to simulate the mechanosensors on EC. Thus, the NO dynamics activated by dynamic shear stresses induced by constant flow, pulsatile flow, and oscillatory flow are analyzed and compared. Moreover, the roles of ROS have been considered for the first time in the modeling of NO dynamics in ECs based on the analysis of cell experiments. The predictions of the proposed model coincide fairly well with the experimental data when ECs are subjected to exercise-induced WSS. The mechanism is elucidated that WSS induced by moderate-intensity exercise is most favorable to NO production in ECs. This study can provide valuable insights for further study of NO and ROS dynamics in ECs and help develop appropriate exercise regimens for improving endothelial functions.
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Affiliation(s)
- Xiao Zeng
- School of Optoelectronic Engineering and Instrumentation Science, Dalian University of Technology, Dalian, 116024, Liaoning, PR China.
| | - Chun-Dong Xue
- School of Optoelectronic Engineering and Instrumentation Science, Dalian University of Technology, Dalian, 116024, Liaoning, PR China.
| | - Yong-Jiang Li
- School of Optoelectronic Engineering and Instrumentation Science, Dalian University of Technology, Dalian, 116024, Liaoning, PR China.
| | - Kai-Rong Qin
- School of Biomedical Engineering, Faculty of Medicine, Dalian University of Technology, Dalian, 116024, Liaoning, PR China.
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24
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Bayo Jimenez MT, Hahad O, Kuntic M, Daiber A, Münzel T. Noise, Air, and Heavy Metal Pollution as Risk Factors for Endothelial Dysfunction. Eur Cardiol 2023; 18:e09. [PMID: 37377448 PMCID: PMC10291605 DOI: 10.15420/ecr.2022.41] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 12/12/2022] [Indexed: 06/29/2023] Open
Abstract
During the last two decades, large epidemiological studies have shown that the physical environment, including noise, air pollution or heavy metals, have a considerable impact on human health. It is known that the most common cardiovascular risk factors are all associated with endothelial dysfunction. Vascular tone, circulation of blood cells, inflammation, and platelet activity are some of the most essential functions regulated by the endothelium that suffer negative effects as a consequence of environmental pollution, causing endothelial dysfunction. In this review, we delineate the impact of environmental risk factors in connection to endothelial function. On a mechanistic level, a significant number of studies suggest the involvement of endothelial dysfunction to fundamentally drive the adverse endothelium health effects of the different pollutants. We focus on well-established studies that demonstrate the negative effects on the endothelium, with a focus on air, noise, and heavy metal pollution. This in-depth review on endothelial dysfunction as a consequence of the physical environment aims to contribute to the associated research needs by evaluating current findings from human and animal studies. From a public health perspective, these findings may also help to reinforce efforts promoting the research for adequate promising biomarkers for cardiovascular diseases since endothelial function is considered a hallmark of environmental stressor health effects.
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Affiliation(s)
- Maria Teresa Bayo Jimenez
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
| | - Omar Hahad
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Rhine-MainMainz, Germany
- Leibniz Institute for Resilience Research (LIR)Mainz, Germany
| | - Marin Kuntic
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
| | - Andreas Daiber
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Rhine-MainMainz, Germany
| | - Thomas Münzel
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Rhine-MainMainz, Germany
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25
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Wang C, Zhou J, Gao D, Wang Y, Guo L, Liang W, Shi N, Cheng R, Wang H, Huang J, Liao J, Hu M. Effects of Long-Term Aerobic Exercise on Perivascular Adipose Tissue Function and Akt/eNOS/NO Pathway in Obese Rats. Artery Res 2023. [DOI: 10.1007/s44200-023-00032-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023] Open
Abstract
Abstract
Background
Perivascular adipose tissue (PVAT) in obesity critically contributes to vascular dysfunction, which might be restored by long-term exercise. Protein kinase B/nitric oxide synthase/nitric oxide (Akt/eNOS/NO) down-regulation within PVAT might be involved in the impaired anti-contractile function of arteries. Therefore, the present study evaluated the effect of long-term aerobic exercise on PVAT function and the potential regulator during this process.
Methods
Male Sprague Dawley rats were divided into normal diet control group (NC), normal diet exercise group (NE), high-fat diet control group (HC), and high-fat diet exercise group (HE) (n = 12 in each group). Upon the establishment of obesity (20 weeks of high-fat diet), exercise program was performed on a treadmill for 17 weeks. After the intervention, circulating biomarkers and PVAT morphology were evaluated. Vascular contraction and relaxation were determined with or without PVAT. Production of NO and the phosphorylations of Akt (Ser473) and eNOS (Ser1177) within PVAT were quantified.
Results
Metabolic abnormalities, systemic inflammation, and circulating adipokines in obesity were significantly restored by long-term aerobic exercise (P < 0.05). The anti-contractile effect of PVAT was significantly enhanced by exercise in obese rats (P < 0.05), which was accompanied by a significant reduction in the PVAT mass and lipid droplet area (P < 0.05). Furthermore, the production of NO was significantly increased, and phosphorylation levels of Akt (Ser473) and eNOS (Ser1177) were also significantly promoted in PVAT by long-term aerobic exercise (P < 0.05).
Conclusion
Long-term aerobic exercise training restored PVAT morphology and anti-contractile function in obese rats, and enhanced the activation of the Akt/eNOS/NO signaling pathway in PVAT.
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26
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The mechanism and therapy of aortic aneurysms. Signal Transduct Target Ther 2023; 8:55. [PMID: 36737432 PMCID: PMC9898314 DOI: 10.1038/s41392-023-01325-7] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 12/15/2022] [Accepted: 01/14/2023] [Indexed: 02/05/2023] Open
Abstract
Aortic aneurysm is a chronic aortic disease affected by many factors. Although it is generally asymptomatic, it poses a significant threat to human life due to a high risk of rupture. Because of its strong concealment, it is difficult to diagnose the disease in the early stage. At present, there are no effective drugs for the treatment of aneurysms. Surgical intervention and endovascular treatment are the only therapies. Although current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm, the specific mechanisms remain unclear. Researchers are further exploring the pathogenesis of aneurysms to find new targets for diagnosis and treatment. To better understand aortic aneurysm, this review elaborates on the discovery history of aortic aneurysm, main classification and clinical manifestations, related molecular mechanisms, clinical cohort studies and animal models, with the ultimate goal of providing insights into the treatment of this devastating disease. The underlying problem with aneurysm disease is weakening of the aortic wall, leading to progressive dilation. If not treated in time, the aortic aneurysm eventually ruptures. An aortic aneurysm is a local enlargement of an artery caused by a weakening of the aortic wall. The disease is usually asymptomatic but leads to high mortality due to the risk of artery rupture.
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27
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Norda S, Papadantonaki R. Regulation of cells of the arterial wall by hypoxia and its role in the development of atherosclerosis. VASA 2023; 52:6-21. [PMID: 36484144 DOI: 10.1024/0301-1526/a001044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The cell's response to hypoxia depends on stabilization of the hypoxia-inducible factor 1 complex and transactivation of nuclear factor kappa-B (NF-κB). HIF target gene transcription in cells resident to atherosclerotic lesions adjoins a complex interplay of cytokines and mediators of inflammation affecting cholesterol uptake, migration, and inflammation. Maladaptive activation of the HIF-pathway and transactivation of nuclear factor kappa-B causes monocytes to invade early atherosclerotic lesions, maintaining inflammation and aggravating a low-oxygen environment. Meanwhile HIF-dependent upregulation of the ATP-binding cassette transporter ABCA1 causes attenuation of cholesterol efflux and ultimately macrophages becoming foam cells. Hypoxia facilitates neovascularization by upregulation of vascular endothelial growth factor (VEGF) secreted by endothelial cells and vascular smooth muscle cells lining the arterial wall destabilizing the plaque. HIF-knockout animal models and inhibitor studies were able to show beneficial effects on atherogenesis by counteracting the HIF-pathway in the cell wall. In this review the authors elaborate on the up-to-date literature on regulation of cells of the arterial wall through activation of HIF-1α and its effect on atherosclerotic plaque formation.
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Affiliation(s)
- Stephen Norda
- Department of Cardiovascular Medicine, University Hospital Münster, Germany
| | - Rosa Papadantonaki
- Emergency Department, West Middlesex University Hospital, Chelsea and Westminster NHS Trust, London, United Kingdom
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28
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Sun M, Gao L, Bai H, Hu W, Zhang X, Xiao J, Deng X, Tao H, Ge P, Qin Y, Zhang D. Association Between Visceral Fat, Blood Pressure and Arterial Stiffness in Patients with HFpEF: A Mediation Analysis. Diabetes Metab Syndr Obes 2023; 16:653-662. [PMID: 36923684 PMCID: PMC10008911 DOI: 10.2147/dmso.s399928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/21/2023] [Indexed: 03/10/2023] Open
Abstract
PURPOSE To investigate the association of visceral fat with arterial stiffness of heart failure patients with preserved ejection fraction (HFpEF) and to evaluate the extent to which this association is mediated by blood pressure (BP). PATIENTS AND METHODS This cross-sectional descriptive study (clinicaltrials.gov identifier: NCT04535726) recruited 94 patients with HFpEF totally from October to December 2020. The obesity-related measurements included visceral fat area (VFA), body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-hip ratio (WC/HC), abdominal circumference (AC), body fat mass and fat percentage. Brachial-ankle pulse wave velocity (baPWV) was used to estimate the degree of arterial stiffness. Mediation analysis was performed to reveal whether the effect of visceral fat area on arterial stiffness can be mediated by BP in patients with HFpEF and the extent to which this association was mediated by BP. RESULTS About 93.6% of HFpEF patients were accompanied with abdominal obesity. Patients in baPWV ≥1800cm/s group were older, with a higher incidence of type 2 diabetes mellitus (T2DM), hypertension and abdominal obesity. VFA, systolic BP (SBP), diastolic BP (DBP) and pulse pressure (PP) were correlated with baPWV in total group. Adjusted for age ≥75 years old, gender, smoking, T2DM, calcium channel blocker and statins, the mediation effect of systolic SBP and PP on the VFA-baPWV association were 53.3% (indirect effect was 2.28, 95% CI 0.62-4.73) and 48.4% (indirect effect was 2.07, 95% CI 0.51-4.38), respectively. DBP failed to mediate the association between VFA and baPWV (indirect effect was 0.50, 95% CI -0.41-2.14). CONCLUSION The association of visceral fat with baPWV in HFpEF patients may be partly accounted for SBP or PP. Elevated SBP and PP might be important potential targets for preventing arterial stiffness in HFpEF patients.
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Affiliation(s)
- Min Sun
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
- Health Management Center, The First Branch of the Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Lei Gao
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Hongmei Bai
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Weiwei Hu
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xiaofang Zhang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Jin Xiao
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xiangliang Deng
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Hongmei Tao
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Ping Ge
- Health Management Center, The First Branch of the Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Yuhong Qin
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Dongying Zhang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
- Correspondence: Dongying Zhang; Yuhong Qin, Tel +86-23-13608398395; +86-23-13068357151, Email ;
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29
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Role of CD40 ligand-mediated endothelial cell-monocyte interaction at atherosclerosis predilection sites. Biochem Pharmacol 2022; 206:115298. [PMID: 36243097 DOI: 10.1016/j.bcp.2022.115298] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Monocyte recruitment into the vessel wall at atherosclerosis predilection sites is essential for lesion development in the early phase of atherosclerosis. Platelets interacting with ultra-large von Willebrand Factor (ULVWF) multimers deposited after CD40 receptor ligation on the endothelial surface form adhesive bridges and facilitate monocyte diapedesis. We hypothesise that enhanced endothelial CD40 expression at arterial bifurcations is responsible for monocyte recruitment and that its absence reduces susceptibility to atherosclerosis. METHODS Y-shaped channel slides covered with endothelial cells (HUVEC) and isolated perfused carotid artery bifurcations from different mouse lines were used for adhesion studies with isolated fluorescent dye-labelled platelets and monocytes. Monocyte adherence was quantified via fluorescence imaging. Oil Red O staining visualised aortic atherosclerotic plaques, and mRNA expression was determined by qRT-PCR. RESULTS In response to soluble CD40 ligand (sCD40L) stimulated ULVWF release, the number of monocytes bound distal to the bifurcation of the Y-slide was 1.8-fold greater than without stimulation. The number of adherent monocytes in sCD40L-treated carotid artery bifurcations was 6 to 12.3-fold greater in ApoE knockout mice as compared to bifurcations derived from CD40/ApoE-deficient or control mice. CD40 mRNA expression was 2-fold higher in carotid artery bifurcations of ApoE knockout mice as compared to the proximal unbranched segment. Introduction of the CD40 knockout into the ApoE-/- background reduced the atherosclerosis burden along the entire aorta of these mice by 60 %. CONCLUSIONS Our data demonstrate the importance of endothelial CD40 expression at atherosclerosis predilection sites for endothelial cell-platelet-monocyte interaction in the early phase of atherosclerosis.
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Li Z, Bi R, Sun S, Chen S, Chen J, Hu B, Jin H. The Role of Oxidative Stress in Acute Ischemic Stroke-Related Thrombosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8418820. [PMID: 36439687 PMCID: PMC9683973 DOI: 10.1155/2022/8418820] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/13/2022] [Accepted: 11/02/2022] [Indexed: 09/22/2023]
Abstract
Acute ischemic stroke is a serious life-threatening disease that affects almost 600 million people each year throughout the world with a mortality of more than 10%, while two-thirds of survivors remain disabled. However, the available treatments for ischemic stroke are still limited to thrombolysis and/or mechanical thrombectomy, and there is an urgent need for developing new therapeutic target. Recently, intravascular oxidative stress, derived from endothelial cells, platelets, and leukocytes, has been found to be tightly associated with stroke-related thrombosis. It not only promotes primary thrombus formation by damaging endothelial cells and platelets but also affects thrombus maturation and stability by modifying fibrin components. Thus, oxidative stress is expected to be a novel target for the prevention and treatment of ischemic stroke. In this review, we first discuss the mechanisms by which oxidative stress promotes stroke-related thrombosis, then summarize the oxidative stress biomarkers of stroke-related thrombosis, and finally put forward an antithrombotic therapy targeting oxidative stress in ischemic stroke.
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Affiliation(s)
- Zhifang Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Rentang Bi
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shuai Sun
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shengcai Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jiefang Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huijuan Jin
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Li Z, Li JN, Li Q, Liu C, Zhou LH, Zhang Q, Xu Y. Cholesterol efflux regulator ABCA1 exerts protective role against high shear stress-induced injury of HBMECs via regulating PI3K/Akt/eNOS signaling. BMC Neurosci 2022; 23:61. [PMCID: PMC9636808 DOI: 10.1186/s12868-022-00748-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 10/26/2022] [Indexed: 11/08/2022] Open
Abstract
Background In brain, microvascular endothelial cells are exposed to various forces, including shear stress (SS). However, little is known about the effects of high shear stress (HSS) on human brain microvascular endothelial cells (HBMECs) and the underlying mechanism. The cholesterol efflux regulator ATP-binding cassette subfamily A member 1 (ABCA1) has been demonstrated to exert protective effect on HBMECs. However, whether ABCA1 is involved in the mechanism underneath the effect of HSS on HBMECs remains obscure. In the present study, a series of experiments were performed to better understand the effect of HSS on cellular processes of HBMECs and the possible involvement of ABCA1 and PI3K/Akt/eNOS in the underlying mechanisms. Results HBMECs were subjected to physiological SS (PSS) or high SS (HSS). Cell migration was evaluated using Transwell assay. Apoptotic HBMECs were detected by flow cytometry or caspase3/7 activity. IL-1β, IL-6, MCP-1 and TNF-α levels were measured by ELISA. RT-qPCR and western blotting were used for mRNA and protein expression detection, respectively. ROS and NO levels were detected using specific detection kits. Compared to PSS, HBMECs exhibited decreased cell viability and migration and increased cell apoptosis, increased levels of inflammatory cytokines, and improved ROS and NO productions after HSS treatment. Moreover, HSS downregulated ABCA1 but upregulated the cholesterol efflux-related proteins MMP9, AQP4, and CYP46 and activated PI3K/Akt/eNOS pathway. Overexpression of ABCA1 in HBMECS inhibited PI3K/Akt/eNOS pathway and counteracted the deleterious effects of HSS. Contrary effects were observed by ABCA1 silencing. Inhibiting PI3K/Akt/eNOS pathway mimicked ABCA1 effects, suggesting that ABCA1 protects HBMECs from HSS via PI3K/Akt/eNOS signaling. Conclusion These results advanced our understanding on the mechanisms of HSS on HBMECs and potentiated ABCA1/PI3K/Akt/eNOS pathway as therapeutic target for cerebrovascular diseases. Supplementary Information The online version contains supplementary material available at 10.1186/s12868-022-00748-2.
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Affiliation(s)
- Zhe Li
- grid.73113.370000 0004 0369 1660Present Address: Neurovascular Center, Changhai Hospital, Naval Medical University, No. 168 Changhai Rd, Shanghai, 200433 China
| | - Jia-Nan Li
- Department of Neurosurgery, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenyang, Liaoning Province China
| | - Qiang Li
- grid.73113.370000 0004 0369 1660Present Address: Neurovascular Center, Changhai Hospital, Naval Medical University, No. 168 Changhai Rd, Shanghai, 200433 China
| | - Chun Liu
- grid.24516.340000000123704535Present Address: Department of Cerebrovascular Diseases, Blue Cross Brain Hospital Affiliated to Tongji University, No. 2880 Qixin Road, Shanghai, 201101 China
| | - Lin-Hua Zhou
- grid.24516.340000000123704535Present Address: Department of Cerebrovascular Diseases, Blue Cross Brain Hospital Affiliated to Tongji University, No. 2880 Qixin Road, Shanghai, 201101 China
| | - Qi Zhang
- grid.24516.340000000123704535Present Address: Department of Cerebrovascular Diseases, Blue Cross Brain Hospital Affiliated to Tongji University, No. 2880 Qixin Road, Shanghai, 201101 China
| | - Yi Xu
- grid.73113.370000 0004 0369 1660Present Address: Neurovascular Center, Changhai Hospital, Naval Medical University, No. 168 Changhai Rd, Shanghai, 200433 China
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Suvorava T, Metry S, Pick S, Kojda G. Alterations in endothelial nitric oxide synthase activity and their relevance to blood pressure. Biochem Pharmacol 2022; 205:115256. [DOI: 10.1016/j.bcp.2022.115256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 12/15/2022]
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Song W, Yuan Y, Tan X, Gu Y, Zeng J, Song W, Xin Z, Fang D, Guan R. Icariside II induces rapid phosphorylation of endothelial nitric oxide synthase via multiple signaling pathways. PeerJ 2022; 10:e14192. [PMID: 36312762 PMCID: PMC9615964 DOI: 10.7717/peerj.14192] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 09/15/2022] [Indexed: 01/24/2023] Open
Abstract
Icariside II, as a favonoid compound derived from epimedium, has been proved to involed in a variety of biological and pharmacological effects such as anti-inflammatory, anti-osteoporosis, anti-oxidation, anti-aging, and anti-cancer but its mechanism is unclear, especially in terms of its effect on post-transcriptional modification of endothelial nitric oxide synthase (eNOS). Phosphorylation of eNOS plays an important role in the synthesis of nitric oxide in endothelial cells, which is closely related to erectile dysfunction, atherosclerosis, Alzheimer's disease, and other diseases. Our study aims to investigate the effect and mechanism of Icariside II on the rapid phosphorylation of eNOS. In this study, human umbilical vein endothelial cells (HUVECs) were stimulated with Icariside II in the presence or absence of multiple inhibitors (1 µM), including LY294002 (PI3K-inhibitor), MK-2206 (AKT-inhibitor), Bisindolylmaleimide X (AMPK-inhibitor), H-89 (CaMKII-inhibitor), KN-62 (PKA-inhibitor), Dorsomorphin (PKC-inhibitor). The proliferation of HUVECs was assessed using cell counting kit-8 (CCK-8). The release of nitric oxide (NO) within HUVECs was detected via fluorescence probe (DAF-FM). Western blot was used to examine the effect of Icariside II on the expression of eNOS, phosphorylation of eNOS, and common signaling pathways proteins. In this study, Icariside II was found to promote the cell proliferation and rapid NO release in HUVECs. The phosphorylation of eNOS-Ser1177 was significantly increased after Icariside II stimulation and reached a peak at 10 min (p < 0.05). Meanwhile, the phosphorylation of eNOS-Thr495 was significantly decreased after 45 min of stimulation (p < 0.05). Following the intervention with multiple inhibitors, it was found that MK-2206 (AKT inhibitor), LY294002 (PI3K inhibitor), KN-62 (AMPK inhibitor), and Bisindolylmaleimide X (PKC inhibitor) could significantly inhibit the phosphorylation of eNOS-Ser1177 caused by Icariside II (p < 0.05), while MK-2206, LY294002, and Bisindolylmaleimide X reversed the alleviated phosphorylation of eNOS-Thr495. We concluded that Icariside can regulate rapid phosphorylation of eNOS- Ser1177 and eNOS-Thr495 via multiple signaling pathways, resulting in the up-regulation of eNOS and the increased release of NO.
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Affiliation(s)
- Wenpeng Song
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Yiming Yuan
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Xiaohui Tan
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Yangyang Gu
- Department of Urology, Peking University First Hospital, Beijing, China
- Department of Radiation Medicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jianyu Zeng
- Department of Dental Implant Center, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Weidong Song
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Zhongcheng Xin
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Dong Fang
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
| | - Ruili Guan
- Department of Urology, Peking University First Hospital, Beijing, China
- Institute of Urology, Peking University, Beijing, China
- Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing, China
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Influence of Shear Stress, Inflammation and BRD4 Inhibition on Human Endothelial Cells: A Holistic Proteomic Approach. Cells 2022; 11:cells11193086. [PMID: 36231049 PMCID: PMC9563250 DOI: 10.3390/cells11193086] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022] Open
Abstract
Atherosclerosis is an important risk factor in the development of cardiovascular diseases. In addition to increased plasma lipid concentrations, irregular/oscillatory shear stress and inflammatory processes trigger atherosclerosis. Inhibitors of the transcription modulatory bromo- and extra-terminal domain (BET) protein family (BETi) could offer a possible therapeutic approach due to their epigenetic mechanism and anti-inflammatory properties. In this study, the influence of laminar shear stress, inflammation and BETi treatment on human endothelial cells was investigated using global protein expression profiling by ion mobility separation-enhanced data independent acquisition mass spectrometry (IMS-DIA-MS). For this purpose, primary human umbilical cord derived vascular endothelial cells were treated with TNFα to mimic inflammation and exposed to laminar shear stress in the presence or absence of the BRD4 inhibitor JQ1. IMS-DIA-MS detected over 4037 proteins expressed in endothelial cells. Inflammation, shear stress and BETi led to pronounced changes in protein expression patterns with JQ1 having the greatest effect. To our knowledge, this is the first proteomics study on primary endothelial cells, which provides an extensive database for the effects of shear stress, inflammation and BETi on the endothelial proteome.
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Wang J, Zeng L, Zhang Y, Qi W, Wang Z, Tian L, Zhao D, Wu Q, Li X, Wang T. Pharmacological properties, molecular mechanisms and therapeutic potential of ginsenoside Rg3 as an antioxidant and anti-inflammatory agent. Front Pharmacol 2022; 13:975784. [PMID: 36133804 PMCID: PMC9483152 DOI: 10.3389/fphar.2022.975784] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/14/2022] [Indexed: 12/06/2022] Open
Abstract
Inflammation and oxidative stress lead to various acute or chronic diseases, including pneumonia, liver and kidney injury, cardiovascular and cerebrovascular diseases, metabolic diseases, and cancer. Ginseng is a well-known and widely used ethnic medicine in Asian countries, and ginsenoside Rg3 is a saponin isolated from Panax ginseng C. A. Meyer, Panax notoginseng, or Panax quinquefolius L. This compound has a wide range of pharmacological properties, including antioxidant and anti-inflammatory activities, which have been evaluated in disease models of inflammation and oxidative stress. Rg3 can attenuate lung inflammation, prevent liver and kidney function damage, mitigate neuroinflammation, prevent cerebral and myocardial ischemia–reperfusion injury, and improve hypertension and diabetes symptoms. The multitarget, multipathway mechanisms of action of Rg3 have been gradually deciphered. This review summarizes the existing knowledge on the anti-inflammatory and antioxidant effects and underlying molecular mechanisms of ginsenoside Rg3, suggesting that ginsenoside Rg3 may be a promising candidate drug for the treatment of diseases with inflammatory and oxidative stress conditions.
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Affiliation(s)
- Jing Wang
- Department of Respiratory, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Li Zeng
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Ying Zhang
- Department of Respiratory, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Wenxiu Qi
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Ziyuan Wang
- Department of Respiratory, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Lin Tian
- Department of Respiratory, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Daqing Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangzhou, China
- *Correspondence: Qibiao Wu, ; Xiangyan Li, ; Tan Wang,
| | - Xiangyan Li
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Qibiao Wu, ; Xiangyan Li, ; Tan Wang,
| | - Tan Wang
- Department of Respiratory, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Qibiao Wu, ; Xiangyan Li, ; Tan Wang,
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Chen H, Chen C, Spanos M, Li G, Lu R, Bei Y, Xiao J. Exercise training maintains cardiovascular health: signaling pathways involved and potential therapeutics. Signal Transduct Target Ther 2022; 7:306. [PMID: 36050310 PMCID: PMC9437103 DOI: 10.1038/s41392-022-01153-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/22/2022] [Accepted: 08/12/2022] [Indexed: 11/09/2022] Open
Abstract
Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases (CVD). Functional and mechanistic studies that employ animal exercise models as well as observational and interventional cohort studies with human participants, have contributed considerably in delineating the essential signaling pathways by which exercise promotes cardiovascular fitness and health. First, this review summarizes the beneficial impact of exercise on multiple aspects of cardiovascular health. We then discuss in detail the signaling pathways mediating exercise's benefits for cardiovascular health. The exercise-regulated signaling cascades have been shown to confer myocardial protection and drive systemic adaptations. The signaling molecules that are necessary for exercise-induced physiological cardiac hypertrophy have the potential to attenuate myocardial injury and reverse cardiac remodeling. Exercise-regulated noncoding RNAs and their associated signaling pathways are also discussed in detail for their roles and mechanisms in exercise-induced cardioprotective effects. Moreover, we address the exercise-mediated signaling pathways and molecules that can serve as potential therapeutic targets ranging from pharmacological approaches to gene therapies in CVD. We also discuss multiple factors that influence exercise's effect and highlight the importance and need for further investigations regarding the exercise-regulated molecules as therapeutic targets and biomarkers for CVD as well as the cross talk between the heart and other tissues or organs during exercise. We conclude that a deep understanding of the signaling pathways involved in exercise's benefits for cardiovascular health will undoubtedly contribute to the identification and development of novel therapeutic targets and strategies for CVD.
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Affiliation(s)
- Huihua Chen
- School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Chen Chen
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, 200444, China
| | - Michail Spanos
- Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Guoping Li
- Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Rong Lu
- School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yihua Bei
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China. .,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, 200444, China.
| | - Junjie Xiao
- Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China. .,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, 200444, China.
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Adams JA, Lopez JR, Nadkarni V, Zolkipli‐Cunningham Z, Ischiropoulos H, Sackner MA. The effects of a motorized passive simulated jogging device on descent of the arterial pulse waveform dicrotic notch: A single arm placebo-controlled cross-over trial. Physiol Rep 2022; 10:e15418. [PMID: 35924333 PMCID: PMC9350470 DOI: 10.14814/phy2.15418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 07/19/2022] [Indexed: 11/06/2023] Open
Abstract
Whole Body Periodic Acceleration (WBPA, pGz), is a bed that moves the body headward to forward, adds pulses to the circulation inducing descent of the dicrotic notch (DN) on the pulse waveform with an increase in a/b ratio (a = the height of the pulse waveform and b = the height of the secondary wave). Since the WBPA is large, heavy, and non-portable, we engineered a portable device (Jogging Device, JD). JD simulates passive jogging and introduces pulsations to the circulation. We hypothesized that JD would increase the a/b ratio during and after its use. In Study A, a single-arm placebo-controlled cross-over trial was conducted in24 adults (53.8 ± 14.4 years) using JD or control (CONT) for 30 min. Blood pressure (BPs and BPd) and photoplethysmograph pulse (a/b) were measured at baseline (BL), during 30 min of JD or CONT, and 5 and 60 min after. In Study B (n = 20, 52.2 ± 7 years), a single-arm observational trial of 7 consecutive days of JD on BP and a/b, measured at BL, and after 7 days of JD and 48 and 72 hr after its discontinuation. In Study A, BPs, and BPd decreased during JD by 13% and 16%, respectively, while in CONT both increased by 2% and 2.5%, respectively. The a/b increased by 2-fold and remained greater than 2-fold at all-time points, with no change in a/b during CONT. In Study B, BPs and BPd decreased by 9% and remained below BL, at 72 hr after discontinuation of JD. DN descent also occurred after 7 days of JD with a/b increase of 80% and remained elevated by 60% for at least 72 h. JD improves acute and longer-term vascular hemodynamics with an increase in a/b, consistent with increased effects of nitric oxide (NO). JD may have significant clinical and public health implications.
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Affiliation(s)
- Jose A. Adams
- Division NeonatologyMt Sinai Medical Center of Greater MiamiMiami BeachFloridaUSA
| | - Jose R. Lopez
- Department of ResearchMt Sinai Medical Center of Greater MiamiMiami BeachFloridaUSA
| | - Vinay Nadkarni
- Anesthesiology, Critical Care, and Pediatrics, The Children's Hospital of PhiladelphiaUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPennsylvaniaUSA
| | - Zarazuela Zolkipli‐Cunningham
- Mitochondrial Medicine Frontier Program (MMFP), Center for Mitochondrial and Epigenomic Medicine (CMEM), Division of Human Genetics, The Children's Hospital of PhiladelphiaUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPennsylvaniaUSA
| | - Harry Ischiropoulos
- Children's Hospital of Philadelphia Research Institute and Division of Neonatology, Departments of Pediatrics and Systems Pharmacology and Translational Therapeutics, the Raymond and Ruth Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Marvin A. Sackner
- Department of ResearchMt Sinai Medical Center of Greater MiamiMiami BeachFloridaUSA
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Hahad O, Bayo Jimenez MT, Kuntic M, Frenis K, Steven S, Daiber A, Münzel T. Cerebral consequences of environmental noise exposure. ENVIRONMENT INTERNATIONAL 2022; 165:107306. [PMID: 35635962 DOI: 10.1016/j.envint.2022.107306] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/09/2022] [Accepted: 05/15/2022] [Indexed: 06/15/2023]
Abstract
The importance of noise exposure as a major environmental determinant of public health is being increasingly recognized. While in recent years a large body evidence has emerged linking environmental noise exposure mainly to cardiovascular disease, much less is known concerning the adverse health effects of noise on the brain and associated neuropsychiatric outcomes. Despite being a relatively new area of investigation, indeed, mounting research and conclusive evidence demonstrate that exposure to noise, primarily from traffic sources, may affect the central nervous system and brain, thereby contributing to an increased risk of neuropsychiatric disorders such as stroke, dementia and cognitive decline, neurodevelopmental disorders, depression, and anxiety disorder. On a mechanistic level, a significant number of studies suggest the involvement of reactive oxygen species/oxidative stress and inflammatory pathways, among others, to fundamentally drive the adverse brain health effects of noise exposure. This in-depth review on the cerebral consequences of environmental noise exposure aims to contribute to the associated research needs by evaluating current findings from human and animal studies. From a public health perspective, these findings may also help to reinforce efforts promoting adequate mitigation strategies and preventive measures to lower the societal consequences of unhealthy environments.
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Affiliation(s)
- Omar Hahad
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany; Leibniz Institute for Resilience Research (LIR), Mainz, Germany.
| | - Maria Teresa Bayo Jimenez
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marin Kuntic
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Katie Frenis
- Boston Children's Hospital and Harvard Medical School, Department of Hematology/Oncology, Boston, MA, USA
| | - Sebastian Steven
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany
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González A, Richards AM, de Boer RA, Thum T, Arfsten H, Hülsmann M, Falcao-Pires I, Díez J, Foo RSY, Chan MY, Aimo A, Anene-Nzelu CG, Abdelhamid M, Adamopoulos S, Anker SD, Belenkov Y, Ben Gal T, Cohen-Solal A, Böhm M, Chioncel O, Delgado V, Emdin M, Jankowska EA, Gustafsson F, Hill L, Jaarsma T, Januzzi JL, Jhund PS, Lopatin Y, Lund LH, Metra M, Milicic D, Moura B, Mueller C, Mullens W, Núñez J, Piepoli MF, Rakisheva A, Ristić AD, Rossignol P, Savarese G, Tocchetti CG, Van Linthout S, Volterrani M, Seferovic P, Rosano G, Coats AJS, Bayés-Genís A. Cardiac remodelling - Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2022; 24:927-943. [PMID: 35334137 DOI: 10.1002/ejhf.2493] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/09/2022] [Accepted: 03/21/2022] [Indexed: 11/10/2022] Open
Abstract
Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.
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Affiliation(s)
- Arantxa González
- Program of Cardiovascular Diseases, CIMA Universidad de Navarra, and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- CIBERCV, Carlos III Institute of Health, Madrid, Spain
| | - A Mark Richards
- Department of medicine, Yong Loo-Lin School of Medicine, National University of Singapore, Singapore
- Christchurch Heart Institute, University of Otago, Dunedin, New Zealand
| | - Rudolf A de Boer
- University Medical Center Groningen, University of Groningen, Department of Cardiology, Groningen, The Netherlands
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS) and Rebirth Center for Translational Regenerative Therapies, Hannover Medical School, Hannover, Germany
- Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany
| | - Henrike Arfsten
- Clinical Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
- German Centre for Cardiovascular Research (DZHK), Berlin, Germany
| | - Martin Hülsmann
- Clinical Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Inês Falcao-Pires
- Department od Surgery and Physiology, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Javier Díez
- Program of Cardiovascular Diseases, CIMA Universidad de Navarra, and IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- CIBERCV, Carlos III Institute of Health, Madrid, Spain
- Departments of Cardiology and Cardiac Surgery, and Nephrology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Roger S Y Foo
- Department of medicine, Yong Loo-Lin School of Medicine, National University of Singapore, Singapore
| | - Mark Y Chan
- Department of medicine, Yong Loo-Lin School of Medicine, National University of Singapore, Singapore
| | - Alberto Aimo
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Chukwuemeka G Anene-Nzelu
- Department of medicine, Yong Loo-Lin School of Medicine, National University of Singapore, Singapore
- Montreal Heart Institute, Montreal, Canada
| | | | - Stamatis Adamopoulos
- 2nd Department of Cardiovascular Medicine, Onassis Cardiac Surgery Center, Athens, Greece
| | - Stefan D Anker
- Department of Cardiology (CVK), and Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | | | - Tuvia Ben Gal
- Cardiology Department, Rabin Medical Center, Beilinson, Israel
| | | | - Michael Böhm
- Universitätsklinikum des Saarlandes, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Saarland University, Homburg/Saar, Germany
| | - Ovidiu Chioncel
- Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu' Bucharest, University of Medicine Carol Davila, Bucharest, Romania
| | - Victoria Delgado
- Institut del Cor, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Michele Emdin
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Ewa A Jankowska
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Finn Gustafsson
- Rigshospitalet-Copenhagen University Hospital, Heart Centre, Department of Cardiology, Copenhagen, Denmark
| | | | | | - James L Januzzi
- Massachusetts General Hospital and Baim Institute for Clinical Research, Boston, MA, USA
| | - Pardeep S Jhund
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland
| | - Yuri Lopatin
- Volgograd State Medical University, Volgograd, Russia
| | - Lars H Lund
- Department of Medicine, Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - Marco Metra
- Cardiology, ASST Spedali Civili; Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Davor Milicic
- University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Brenda Moura
- Faculty of Medicine, University of Porto, Porto, Portugal
- Cardiology Department, Porto Armed Forces Hospital, Portugal
| | | | | | - Julio Núñez
- CIBERCV, Carlos III Institute of Health, Madrid, Spain
- Hospital Clínico Universitario de Valencia, INCLIVA, Universidad de Valencia, Valencia, Spain
| | - Massimo F Piepoli
- Cardiology Division, Castelsangiovanni Hospital, Castelsangiovanni, Italy
| | - Amina Rakisheva
- Scientific Research Institute of Cardiology and Internal Medicine, Almaty, Kazakhstan
| | - Arsen D Ristić
- Department of Cardiology, University Clinical Center of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Patrick Rossignol
- Université de Lorraine, Centre d'Investigations Cliniques- Plurithématique 1433, and Inserm U1116, CHRU Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Gianluigi Savarese
- Department of Medicine, Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
| | - Carlo G Tocchetti
- Cardio-Oncology Unit, Department of Translational Medical Sciences, Center for Basic and Clinical Immunology Research (CISI), Interdepartmental Center of Clinical and Translational Sciences (CIRCET), Interdepartmental Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy
| | - Sophie Van Linthout
- German Centre for Cardiovascular Research (DZHK), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany
| | | | - Petar Seferovic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Giuseppe Rosano
- St. George's Hospitals, NHS Trust, University of London, London, UK
| | | | - Antoni Bayés-Genís
- CIBERCV, Carlos III Institute of Health, Madrid, Spain
- Institut del Cor, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
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Tian JJ, Levy M, Zhang X, Sinnott R, Maddela R. Counteracting Health Risks by Modulating Homeostatic Signaling. Pharmacol Res 2022; 182:106281. [PMID: 35661711 DOI: 10.1016/j.phrs.2022.106281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/14/2022] [Accepted: 05/27/2022] [Indexed: 10/18/2022]
Abstract
Homeostasis was initially conceptualized by Bernard and Cannon around a century ago as a steady state of physiological parameters that vary within a certain range, such as blood pH, body temperature, and heart rate1,2. The underlying mechanisms that maintain homeostasis are explained by negative feedbacks that are executed by the neuronal, endocrine, and immune systems. At the cellular level, homeostasis, such as that of redox and energy steady state, also exists and is regulated by various cell signaling pathways. The induction of homeostatic mechanism is critical for human to adapt to various disruptive insults (stressors); while on the other hand, adaptation occurs at the expense of other physiological processes and thus runs the risk of collateral damages, particularly under conditions of chronic stress. Conceivably, anti-stress protection can be achieved by stressor-mimicking medicinals that elicit adaptive responses prior to an insult and thereby serve as health risk countermeasures; and in situations where maladaptation may occur, downregulating medicinals could be used to suppress the responses and prevent subsequent pathogenesis. Both strategies are preemptive interventions particularly suited for individuals who carry certain lifestyle, environmental, or genetic risk factors. In this article, we will define and characterize a new modality of prophylactic intervention that forestalls diseases via modulating homeostatic signaling. Moreover, we will provide evidence from the literature that support this concept and distinguish it from other homeostasis-related interventions such as adaptogen, hormesis, and xenohormesis.
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Affiliation(s)
- Junqiang J Tian
- USANA Health Science, Inc., 3838 Parkway Blvd, Salt Lake City, UT 84121, USA.
| | - Mark Levy
- USANA Health Science, Inc., 3838 Parkway Blvd, Salt Lake City, UT 84121, USA
| | - Xuekai Zhang
- Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing100029, China; US Center for Chinese Medicine, 14801 Physicians lane, 171 A 2nd Floor, #281, Rockville MD 20850, USA
| | - Robert Sinnott
- USANA Health Science, Inc., 3838 Parkway Blvd, Salt Lake City, UT 84121, USA
| | - Rolando Maddela
- USANA Health Science, Inc., 3838 Parkway Blvd, Salt Lake City, UT 84121, USA
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Piacenza L, Zeida A, Trujillo M, Radi R. The superoxide radical switch in the biology of nitric oxide and peroxynitrite. Physiol Rev 2022; 102:1881-1906. [PMID: 35605280 DOI: 10.1152/physrev.00005.2022] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Lucìa Piacenza
- Departamento de Bioquímica, Facultad de Medicina; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Uruguay
| | - Ari Zeida
- Departamento de Bioquímica, Facultad de Medicina; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
| | - Madia Trujillo
- Departamento de Bioquímica, Facultad de Medicina; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
| | - Rafael Radi
- Departamento de Bioquímica, Facultad de Medicina; Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Montevideo, Uruguay
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Kovarnik T, Hitoshi M, Kral A, Jerabek S, Zemanek D, Kawase Y, Omori H, Tanigaki T, Pudil J, Vodzinska A, Branny M, Stipal R, Kala P, Mrozek J, Porzer M, Grezl T, Novobilsky K, Mendiz O, Kopriva K, Mates M, Chval M, Chen Z, Martasek P, Linhart A. Fractional Flow Reserve Versus Instantaneous Wave-Free Ratio in Assessment of Lesion Hemodynamic Significance and Explanation of their Discrepancies. International, Multicenter and Prospective Trial: The FiGARO Study. J Am Heart Assoc 2022; 11:e021490. [PMID: 35502771 PMCID: PMC9238629 DOI: 10.1161/jaha.121.021490] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Background The FiGARO (FFR versus iFR in Assessment of Hemodynamic Lesion Significance, and an Explanation of Their Discrepancies) trial is a prospective registry searching for predictors of fractional flow reserve/instantaneous wave‐free ratio (FFR/iFR) discrepancy. Methods and Results FFR/iFR were analyzed using a Verrata wire, and coronary flow reserve was analyzed using a Combomap machine (both Philips‐Volcano). The risk polymorphisms for endothelial nitric oxide synthase and for heme oxygenase‐1 were analyzed. In total, 1884 FFR/iFR measurements from 1564 patients were included. The FFR/iFR discrepancy occurred in 393 measurements (20.9%): FFRp (positive)/iFRn (negative) type (264 lesions, 14.0%) and FFRn/iFRp (129 lesions, 6.8%) type. Coronary flow reserve was measured in 343 lesions, correlating better with iFR (R=0.56, P<0.0001) than FFR (R=0.36, P<0.0001). The coronary flow reserve value in FFRp/iFRn lesions (2.24±0.7) was significantly higher compared with both FFRp/iFRp (1.39±0.36), and FFRn/iFRn lesions (1.8±0.64, P<0.0001). Multivariable logistic regression analysis confirmed (1) sex, age, and lesion location in the right coronary artery as predictors for FFRp/iFRn discrepancy; and (2) hemoglobin level, smoking, and renal insufficiency as predictors for FFRn/iFRp discrepancy. The FFRn/iFRp type of discrepancy was significantly more frequent in patients with both risk types of polymorphisms (endothelial nitric oxide synthaser+heme oxygenase‐1r): 8 patients (24.2%) compared with FFRp/iFRn type of discrepancy: 2 patients (5.9%), P=0.03. Conclusions Predictors for FFRp/iFRn discrepancy were sex, age, and location in the right coronary artery. Predictors for FFRn/iFRp were hemoglobin level, smoking, and renal insufficiency. The risk type of polymorphism in endothelial nitric oxide synthase and heme oxygenase‐1 genes was more frequently found in patients with FFRn/iFRp type of discrepancy. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT03033810.
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Affiliation(s)
- Tomas Kovarnik
- 2nd Department of Medicine Department of Cardiovascular Medicine First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic
| | | | - Ales Kral
- 2nd Department of Medicine Department of Cardiovascular Medicine First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic
| | - Stepan Jerabek
- 2nd Department of Medicine Department of Cardiovascular Medicine First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic
| | - David Zemanek
- 2nd Department of Medicine Department of Cardiovascular Medicine First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic
| | | | | | | | - Jan Pudil
- 2nd Department of Medicine Department of Cardiovascular Medicine First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic
| | | | - Marian Branny
- Cardiovascular Department University Hospital Ostrava Ostrava Czech Republic
| | - Roman Stipal
- Department of Internal Medicine and Cardiology University HospitalFaculty of MedicineMasaryk University Brno Brno Czech Republic
| | - Petr Kala
- Department of Internal Medicine and Cardiology University HospitalFaculty of MedicineMasaryk University Brno Brno Czech Republic
| | - Jan Mrozek
- Cardiovascular Department University Hospital Ostrava Ostrava Czech Republic
| | - Martin Porzer
- Cardiovascular Department University Hospital Ostrava Ostrava Czech Republic
| | - Tomas Grezl
- Cardiovascular Department University Hospital Ostrava Ostrava Czech Republic
| | - Kamil Novobilsky
- Cardiology Department Municipal Hospital Ostrava Ostrava Czech Republic
| | | | - Karel Kopriva
- Cardiology Department Homolka Hospital Prague Czech Republic
| | - Martin Mates
- Cardiology Department Homolka Hospital Prague Czech Republic
| | - Martin Chval
- Institute for Research and Development of Education Faculty of Education Charles University Prague Czech Republic
| | - Zhi Chen
- Department of Electrical & Computer Engineering Iowa Institute for Biomedical ImagingThe University of Iowa IA
| | - Pavel Martasek
- Department of Paediatrics and Inherited Metabolic Disorders First Faculty of Medicine Charles UniversityGeneral University Hospital Prague Czech Republic
| | - Ales Linhart
- 2nd Department of Medicine Department of Cardiovascular Medicine First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic
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Abdelilah-Seyfried S, Iruela-Arispe ML, Penninger JM, Tournier-Lasserve E, Vikkula M, Cleaver O. Recalibrating vascular malformations and mechanotransduction by pharmacological intervention. J Clin Invest 2022; 132:e160227. [PMID: 35426368 PMCID: PMC9012280 DOI: 10.1172/jci160227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
| | - M. Luisa Iruela-Arispe
- Department of Cell and Developmental Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Josef M. Penninger
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Elisabeth Tournier-Lasserve
- INSERM UMR 1141 Neurodiderot, University of Paris, Paris, France
- AP-HP, Department of Genetics of Neurovascular Diseases, Hôpital Saint-Louis, Paris, France
| | - Miikka Vikkula
- Human Molecular Genetics, de Duve Institute, Brussels, Belgium
| | - Ondine Cleaver
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas, USA
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Saito Y, Otaki Y, Watanabe T, Wanezaki M, Kutsuzawa D, Kato S, Tamura H, Nishiyama S, Arimoto T, Takahashi H, Ueno Y, Konta T, Watanabe M. Effects of Nitric Oxide Synthase 3 Gene Polymorphisms on Cardiovascular Events in a General Japanese Population ― The Yamagata (Takahata) Study ―. Circ Rep 2022; 4:222-229. [PMID: 35600721 PMCID: PMC9072097 DOI: 10.1253/circrep.cr-21-0159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/28/2022] [Accepted: 03/16/2022] [Indexed: 11/09/2022] Open
Abstract
Background: Single nucleotide polymorphisms (SNPs) in nitric oxide synthase 3 (NOS3) are associated with cardiovascular risk factors. However, it is not clear whether the NOS3 SNP is a genetic risk factor for cardiovascular diseases. Methods and Results: This prospective cohort study included 2,726 subjects aged ≥40 years who participated in a community-based health checkup. We genotyped 639 SNPs, including 2 NOS3 SNPs (rs1799983 and rs1808593). All subjects were monitored prospectively over a median follow-up period of 16.0 years, with the endpoint being cardiovascular events, including cardiovascular death and/or non-fatal myocardial infarction. Kaplan-Meier analysis demonstrated that both rs1799983 GT/TT and rs1808593 GG carriers had a higher risk of the endpoint than non-carriers. Univariate and multivariate Cox proportional hazard regression analyses revealed that both rs1799983 GT/TT and rs1808593 GG were independently associated with cardiovascular events after adjusting for confounding risk factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of NOS3 SNPs as cardiovascular risk factors. Conclusions:NOS3 gene polymorphisms could be genetic risk factors for cardiovascular events in the general Japanese population, and could be used to facilitate the early identification of individuals at high risk of cardiovascular events.
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Affiliation(s)
- Yuji Saito
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Yoichiro Otaki
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Tetsu Watanabe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Masahiro Wanezaki
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Daisuke Kutsuzawa
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Shigehiko Kato
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Harutoshi Tamura
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Satoshi Nishiyama
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Takanori Arimoto
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Hiroki Takahashi
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
| | - Yoshiyuki Ueno
- Global Center of Excellence, Yamagata University School of Medicine
| | - Tsuneo Konta
- Department of Public Health and Hygiene, Yamagata University Graduate School of Medical Science
| | - Masafumi Watanabe
- Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine
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Biopaper Based on Ultralong Hydroxyapatite Nanowires and Cellulose Fibers Promotes Skin Wound Healing by Inducing Angiogenesis. COATINGS 2022. [DOI: 10.3390/coatings12040479] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Skin injury that is difficult to heal caused by various factors remains a major clinical challenge. Hydroxyapatite (HAP) has high potential for wound healing owing to its high biocompatibility and adequate angiogenic ability, while traditional HAP materials are not suitable for wound dressing due to their high brittleness and poor mechanical properties. To address this challenge, we developed a novel wound dressing made of flexible ultralong HAP nanowire-based biopaper. This biopaper is flexible and superhydrophilic, with suitable tensile strength (2.57 MPa), high porosity (77%), and adequate specific surface area (36.84 m2·g−1) and can continuously release Ca2+ ions to promote the healing of skin wounds. Experiments in vitro and in vivo show that the ultralong HAP nanowire-based biopaper can effectively induce human umbilical vein endothelial cells (HUVECs) treated with hypoxia and rat skin tissue to produce more angiogenic factors. The as-prepared biopaper can also enhance the proliferation, migration, and in vitro angiogenesis of HUVECs. In addition, the biopaper can promote the rat skin to achieve thicker skin re-epithelialization and the formation of new blood vessels, and thus promote the healing of the wound. Therefore, the ultralong HAP nanowire-based biopaper has the potential to be a safe and effective wound dressing and has significant clinical application prospects.
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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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MacKay CE, Floen M, Leo MD, Hasan R, Garrud TAC, Fernández-Peña C, Singh P, Malik KU, Jaggar JH. A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation. eLife 2022; 11:e74765. [PMID: 35229718 PMCID: PMC8933003 DOI: 10.7554/elife.74765] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 02/25/2022] [Indexed: 11/25/2022] Open
Abstract
Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the Pkd1 gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms, and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific Pkd1 knockout (Pkd1 ecKO) mice, we show that flow activates PC-1-mediated, Ca2+-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and via the activation of endothelial nitric oxide synthase (eNOS) and intermediate (IK)- and small (SK)-conductance Ca2+-activated K+ channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (Pkd2 ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (Pkd1/Pkd2 ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates nonselective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility through the formation of an interdependent signaling complex with PC-2 in ECs. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to eNOS, IK channel, and SK channel activation, vasodilation, and a reduction in blood pressure.
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Affiliation(s)
- Charles E MacKay
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Miranda Floen
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
| | - M Dennis Leo
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Raquibul Hasan
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Tessa AC Garrud
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Carlos Fernández-Peña
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Purnima Singh
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Kafait U Malik
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
| | - Jonathan H Jaggar
- Department of Physiology, University of Tennessee Health Science CenterMemphisUnited States
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Tryfonos A, Rasoul D, Sadler D, Shelley J, Mills J, Green DJ, Dawson EA, Cocks M. Elevated shear rate-induced by exercise increases eNOS ser 1177 but not PECAM-1 Tyr 713 phosphorylation in human conduit artery endothelial cells. Eur J Sport Sci 2022; 23:561-570. [PMID: 35195045 DOI: 10.1080/17461391.2022.2046175] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Although evidence demonstrates the fundamental role of shear stress in vascular health, predominantly through the release of nitric oxide (NO), the mechanisms by which endothelial cells (EC)s sense and transduce shear are poorly understood. In cultured ECs tyrosine phosphorylation of PECAM-1 has been shown to activate eNOS in response to shear stress. However, in the human skeletal muscle microcirculation PECAM-1 was not activated in response to exercise or passive leg movement. Given this contradiction, this study aimed to assess the effect of exercise on conduit artery PECAM-1 and eNOS activation in humans. Eleven males were randomised to two groups; 30 minutes of handgrip exercise (n = 6), or a time-control group (n = 5). Protein content of eNOS and PECAM-1, alongside eNOS Ser1177 and PECAM-1 Tyr713 phosphorylation were assessed in ECs obtained from the radial artery pre- and post-intervention. Handgrip exercise resulted in a 5-fold increase in mean shear rate in the exercise group, with no change in the control group (group*time, P < 0.001). There was a 54% increase in eNOS Ser1177 phosphorylation in the exercise group, when compared to control group (group*time, P = 0.016), but no change was reported in PECAM-1 Tyr713 phosphorylation in either group (group*time, P > 0.05). eNOS and PECAM-1 protein content were unchanged (group*time, P > 0.05). Our data show that exercise-induced elevations in conduit artery shear rate increase eNOS Ser1177 phosphorylation but not PECAM-1 Tyr713 phosphorylation. This suggests PECAM-1 phosphorylation may not be involved in the vascular response to acute but prolonged elevations in exercise-induced shear rate in conduit arteries of healthy, active men.
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Affiliation(s)
- Andrea Tryfonos
- Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom
| | - Debar Rasoul
- Liverpool Heart and Chest Hospital, Liverpool L14 3PE, United Kingdom
| | - Daniel Sadler
- Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom
| | - James Shelley
- Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom
| | - Joseph Mills
- Liverpool Heart and Chest Hospital, Liverpool L14 3PE, United Kingdom
| | - Daniel J Green
- School of Human Sciences (Exercise and Sport Science), The University of Western Australia, Crawley, Western Australia, 6009, Australia
| | - Ellen A Dawson
- Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom
| | - Matthew Cocks
- Research Institute for Sport and Exercise Science, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom
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Shi J, Ren Y, Liu S, Zhao Q, Kong F, Guo Y, Xu J, Liu S, Qiao Y, Li Y, Liu Y, Liu Y, Cheng Y. Circulating miR-3656 induces human umbilical vein endothelial cell injury by targeting eNOS and ADAMTS13: a novel biomarker for hypertension. J Hypertens 2022; 40:310-317. [PMID: 34475349 DOI: 10.1097/hjh.0000000000003010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hypertension, as one of the most common chronic diseases, is a major public health issue. Previous studies have shown that there are miRNAs differentially expressed in hypertensive patients. In addition, hypertension is closely related to endothelial dysfunction, and miRNAs have been identified as important molecular mediators for endothelial function. Therefore, it is necessary to identify specific miRNAs related to hypertension and explore their molecular mechanism in the progression of hypertension. METHODS We investigated the association of circulating levels of miR-3656 with hypertension. Furthermore, in-vitro studies were performed to investigate its possible mechanisms for hypertension in that the direct target genes of miR-3656 were confirmed using dual-luciferase reporter assay; moreover, the effects of miR-3656 on proliferation, migration, apoptosis, and microvascular rarefaction of HUVECs were investigated using MTS kit, wound-healing assay, FITC Annexin V apoptosis detection kit, and tube formation assay, correspondingly. RESULTS Circulating miR-3656 was upregulated in patients with hypertension. MiR-3656 suppressed the proliferation, migration, and angiogenesis of HUVECs, but promoted the apoptosis of HUVECs. In addition, eNOS and ADAMTS13 were direct target genes of miR-3656, and overexpression of eNOS and ADAMTS13 abolished the effect of miR-3656 on HUVECs. CONCLUSION MiR-3656 is a potential biomarker for hypertension. MiR-3656 is involved in endothelial cellular injury implicated in hypertension by targeting eNOS and ADAMTS13.
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Affiliation(s)
- Jikang Shi
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yaxuan Ren
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Sainan Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Qian Zhao
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Fei Kong
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yanbo Guo
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Jiayi Xu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Siyu Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yichun Qiao
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yong Li
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yunkai Liu
- The Cardiovascular Center, the First Hospital of Jilin University, Changchun, China
| | - Yawen Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Jilin University
| | - Yi Cheng
- The Cardiovascular Center, the First Hospital of Jilin University, Changchun, China
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High Output Heart Failure in Multiple Myeloma: Pathogenetic Considerations. Cancers (Basel) 2022; 14:cancers14030610. [PMID: 35158878 PMCID: PMC8833382 DOI: 10.3390/cancers14030610] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/19/2022] [Accepted: 01/21/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Multiple myeloma is a plasma cell disorder that accounts for around 10% of all haematological malignancies. This neoplasia is often associated with a significant prevalence of cardiovascular complications resulting from several factors, unrelated and/or related to the disease. Among cardiovascular complications, the high output heart failure is of great importance as it is related to a worse prognosis for patients. It is important to point out that, despite the availability of more and more numerous and effective drugs, myeloma remains an incurable disease, with frequent relapses and several treatment lines, with the need, therefore, for a careful evaluation of patients, especially from a cardiological point of view. For this reason, we are proposing a comprehensive overview of different pathogenetic mechanisms responsible for high output heart failure in multiple myeloma, including artero-venous shunts, enhanced angiogenesis, glutamminolysis, hyperammonemia and hemorheological alterations, with the belief that a multidisciplinary approach, in clinical evaluation is critical for the optimal management of the patient. Abstract The high output heart failure is a clinical condition in which the systemic congestion is associated to a high output state, and it can be observed in a non-negligible percentage of hematological diseases, particularly in multiple myeloma, a condition in which the risk of adverse cardiovascular events may increase, with a worse prognosis for patients. For this reason, though an accurate literature search, we provided in this review a complete overview of different pathogenetic mechanisms responsible for high output heart failure in multiple myeloma. Indeed, this clinical finding is present in the 8% of multiple myeloma patients, and it may be caused by artero-venous shunts, enhanced angiogenesis, glutamminolysis, hyperammonemia and hemorheological alterations with increase in plasma viscosity. The high output heart failure in multiple myeloma is associated with significant morbidity and mortality, emphasizing the need for a multidisciplinary approach.
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