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Wang X, Chai Y, Dou Y, Li X, Li F, Gao K. Global trends and hotspots in macrophage research related to hypertension from 2015-2024: bibliometric research and visualization analysis. Front Immunol 2025; 16:1501432. [PMID: 40109339 PMCID: PMC11920128 DOI: 10.3389/fimmu.2025.1501432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 02/11/2025] [Indexed: 03/22/2025] Open
Abstract
Background Hypertension continues to be a global health and economic burden, conventionally characterized by a chronic inflammatory state. Macrophages are critical for the initiation, progression and manifestation of hypertension. As studies on the relationship between macrophages and hypertension increase substantially, identifying critical research areas and unraveling potential interaction mechanisms become increasingly essential. Methods Articles associated with hypertension and macrophages in recent 10 years were retrieved from the Web of Science Core Collection for analysis, using Microsoft Excel, VOSviewer, CiteSpace and Scimago Graphica. Results After excluding studies that did not meet inclusive standard based on time (2015-2024) and type (article or reviews), 2,013 original articles related to macrophages associated with hypertension were included. The number of publications has been increasing annually. These records consisted of 2,013 English language papers published in 351 journals by 315 institutions or regions from 83 countries/regions between 2015 and 2024. We analyzed the co-cited references clusters to objectively outline the current state of research, including the regulatory mechanisms of hypertension, diseases related to hypertension, and the lifestyle factor. Inflammation remains one of the most popular research hot-spot. The most popular publishing journal in this field is PLOS ONE and the most prolific writer is Li, Hui-Hua. The primary keywords cluster in this field is inflammation, with the highest occurrences and TLS among the top 10 keywords. Conclusion These comprehensive and visualized bibliometric results summarized the significant findings in macrophage-related hypertension studies over the past 10 years. Macrophages appear to be effective in the treatment of hypertension as potential targets, but further research is needed to clarify the specific pathophysiological mechanisms involved.
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Affiliation(s)
| | | | | | | | - Fanghe Li
- Beijing University of Chinese Medicine, Beijing, China
| | - Kuo Gao
- Beijing University of Chinese Medicine, Beijing, China
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Dousdampanis P, Aggeletopoulou I, Mouzaki A. The role of M1/M2 macrophage polarization in the pathogenesis of obesity-related kidney disease and related pathologies. Front Immunol 2025; 15:1534823. [PMID: 39867890 PMCID: PMC11758166 DOI: 10.3389/fimmu.2024.1534823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 12/19/2024] [Indexed: 01/28/2025] Open
Abstract
Obesity is a rapidly growing health problem worldwide, affecting both adults and children and increasing the risk of chronic diseases such as type 2 diabetes, hypertension and cardiovascular disease (CVD). In addition, obesity is closely linked to chronic kidney disease (CKD) by either exacerbating diabetic complications or directly causing kidney damage. Obesity-related CKD is characterized by proteinuria, lipid accumulation, fibrosis and glomerulosclerosis, which can gradually impair kidney function. Among the immune cells of the innate and adaptive immune response involved in the pathogenesis of obesity-related diseases, macrophages play a crucial role in the inflammation associated with CKD. In obese individuals, macrophages enter a pro-inflammatory state known as M1 polarization, which contributes to chronic inflammation. This polarization promotes tissue damage, inflammation and fibrosis, leading to progressive loss of kidney function. In addition, macrophage-induced oxidative stress is a key feature of CKD as it also promotes cell damage and inflammation. Macrophages also contribute to insulin resistance in type 2 diabetes by releasing inflammatory molecules that impair glucose metabolism, complicating the management of diabetes in obese patients. Hypertension and atherosclerosis, which are often associated with obesity, also contribute to the progression of CKD via immune and inflammatory pathways. Macrophages influence blood pressure regulation and contribute to vascular inflammation, particularly via the renin-angiotensin system. In atherosclerosis, macrophages accumulate in arterial plaques, leading to chronic inflammation and plaque instability, which may increase the risk of CVD in CKD patients. This review focuses on the involvement of macrophages in CKD and highlights their role as a critical link between CKD and other pathologies. Targeting macrophage polarization and the ensuing macrophage-induced inflammation could be an effective therapeutic strategy for CKD and related diseases and improve outcomes for patients with obesity-related kidney disease.
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Affiliation(s)
| | - Ioanna Aggeletopoulou
- Laboratory of Immunohematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Laboratory of Immunohematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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Brobak KM, Halvorsen LV, Aass HCD, Søraas CL, Aune A, Olsen E, Bergland OU, Rognstad S, Blom KB, Birkeland JAK, Høieggen A, Larstorp ACK, Solbu MD. Novel biomarkers in patients with uncontrolled hypertension with and without kidney damage. Blood Press 2024; 33:2323980. [PMID: 38606688 DOI: 10.1080/08037051.2024.2323980] [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: 11/15/2023] [Accepted: 02/20/2024] [Indexed: 04/13/2024]
Abstract
INTRODUCTION Estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (ACR) are insensitive biomarkers for early detection of hypertension-mediated organ damage (HMOD). In this nationwide cross-sectional study, we assessed potential biomarkers for early HMOD in healthy persons and patients with hypertension. We hypothesised that plasma levels of biomarkers: (1) are different between healthy controls and patients with hypertension, (2): can classify patients with hypertension according to the degree of hypertension severity. DESIGN AND METHODS Patients with hypertension prescribed ≥2 antihypertensive agents were selected from a multicentre study. Healthy controls were selected from an ongoing study of living kidney donor candidates. Uncontrolled hypertension was defined as systolic daytime ambulatory blood pressure ≥135 mmHg. Kidney HMOD was defined by ACR > 3.0 mg/mmol or eGFR < 60 mL/min/1.73 m2. Patients with hypertension were categorised into three groups: (1) controlled hypertension; (2) uncontrolled hypertension without kidney HMOD; (3) uncontrolled hypertension with kidney HMOD. Fifteen biomarkers were analysed using a Luminex bead-based immunoassay, and nine fell within the specified analytical range. RESULTS Plasma levels of Interleukin 1 receptor antagonist (IL-1RA), neutrophil gelatinase-associated lipocalin (NGAL) and uromodulin were significantly different between healthy controls (n = 39) and patients with hypertension (n = 176). In regression models, with controlled hypertension (n = 55) as the reference category, none of the biomarkers were associated with uncontrolled hypertension without (n = 59) and with (n = 62) kidney HMOD. In models adjusted for cardiovascular risk factors and eGFR, osteopontin (OPN) was associated with uncontrolled hypertension without kidney HMOD (odds ratio (OR) 1.77 (1.05-2.98), p = 0.03), and regulated upon activation normal T-cell expressed and secreted (RANTES) with uncontrolled hypertension with kidney HMOD (OR 0.57 (0.34-0.95), p = 0.03). CONCLUSIONS None of the biomarkers could differentiate our hypertension groups when established risk factors were considered. Plasma OPN may identify patients with uncontrolled hypertension at risk for kidney HMOD.
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Affiliation(s)
- Karl Marius Brobak
- Section of Nephrology, University Hospital of North Norway, Tromsø, Norway
- Metabolic and Renal Research Group, UiT The Artic University of Norway, Tromsø, Norway
| | - Lene V Halvorsen
- Department of Nephrology, Oslo University Hospital Ullevål, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section for Cardiovascular and Renal Research, Oslo University Hospital Ullevål, Oslo, Norway
| | | | - Camilla L Søraas
- Section for Cardiovascular and Renal Research, Oslo University Hospital Ullevål, Oslo, Norway
- Section for Environmental and Occupational Medicine, Oslo University Hospital Ullevål, Oslo, Norway
| | - Arleen Aune
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Eirik Olsen
- Clinic of Emergency Medicine and Prehospital Care, Trondheim University Hospital, Trondheim, Norway
- Department of Circulation and Medical Imaging, University of Trondheim, Trondheim, Norway
| | - Ola Undrum Bergland
- Section for Cardiovascular and Renal Research, Oslo University Hospital Ullevål, Oslo, Norway
| | - Stine Rognstad
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section for Cardiovascular and Renal Research, Oslo University Hospital Ullevål, Oslo, Norway
- Department of Pharmacology, Oslo University Hospital Ullevål, Oslo, Norway
| | - Kjersti B Blom
- Department of Nephrology, Oslo University Hospital Ullevål, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Institute for Experimental Medical Research, and KG Jebsen Center for Cardiac Research, Oslo University Hospital, Ullevål and University of Oslo, Oslo, Norway
| | | | - Aud Høieggen
- Department of Nephrology, Oslo University Hospital Ullevål, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section for Cardiovascular and Renal Research, Oslo University Hospital Ullevål, Oslo, Norway
| | - Anne Cecilie K Larstorp
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section for Cardiovascular and Renal Research, Oslo University Hospital Ullevål, Oslo, Norway
- Department of Medical Biochemistry, Oslo University Hospital Ullevål, Oslo, Norway
| | - Marit D Solbu
- Section of Nephrology, University Hospital of North Norway, Tromsø, Norway
- Metabolic and Renal Research Group, UiT The Artic University of Norway, Tromsø, Norway
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Smith HL, Goodlett BL, Navaneethabalakrishnan S, Mitchell BM. Elevated Salt or Angiotensin II Levels Induce CD38+ Innate Immune Cells in the Presence of Granulocyte-Macrophage Colony Stimulating Factor. Cells 2024; 13:1302. [PMID: 39120331 PMCID: PMC11311366 DOI: 10.3390/cells13151302] [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: 07/08/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024] Open
Abstract
Hypertension (HTN) impacts almost half of adults, predisposing them to cardiovascular disease and renal damage. Salt-sensitive HTN (SSHTN) and angiotensin II (A2)-induced HTN (A2HTN) both involve immune system activation and renal innate immune cell infiltration. Subpopulations of activated [Cluster of differentiation 38 (CD38)] innate immune cells, such as macrophages and dendritic cells (DCs), play distinct roles in modulating renal function and blood pressure. It is unknown how these cells become CD38+ or which subtypes are pro-hypertensive. When bone marrow-derived monocytes (BMDMs) were grown in granulocyte-macrophage colony stimulating factor (GM-CSF) and treated with salt or A2, CD38+ macrophages and CD38+ DCs increased. The adoptive transfer of GM-CSF-primed BMDMs into mice with either SSHTN or A2HTN increased renal CD38+ macrophages and CD38+ DCs. Flow cytometry revealed increased renal M1 macrophages and type-2 conventional DCs (cDC2s), along with their CD38+ counterparts, in mice with either SSHTN or A2HTN. These results were replicable in vitro. Either salt or A2 treatment of GM-CSF-primed BMDMs significantly increased bone marrow-derived (BMD)-M1 macrophages, CD38+ BMD-M1 macrophages, BMD-cDC2s, and CD38+ BMD-cDC2s. Overall, these data suggest that GM-CSF is necessary for the salt or A2 induction of CD38+ innate immune cells, and that CD38 distinguishes pro-hypertensive immune cells. Further investigation of CD38+ M1 macrophages and CD38+ cDC2s could provide new therapeutic targets for both SSHTN and A2HTN.
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Affiliation(s)
| | | | | | - Brett M. Mitchell
- Department of Medical Physiology, Texas A&M School of Medicine, Bryan, TX 77807, USA; (H.L.S.)
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Nguyen BA, Alexander MR, Harrison DG. Immune mechanisms in the pathophysiology of hypertension. Nat Rev Nephrol 2024; 20:530-540. [PMID: 38658669 PMCID: PMC12060254 DOI: 10.1038/s41581-024-00838-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2024] [Indexed: 04/26/2024]
Abstract
Hypertension is a leading risk factor for morbidity and mortality worldwide. Despite current anti-hypertensive therapies, most individuals with hypertension fail to achieve adequate blood pressure control. Moreover, even with adequate control, a residual risk of cardiovascular events and associated organ damage remains. These findings suggest that current treatment modalities are not addressing a key element of the underlying pathology. Emerging evidence implicates immune cells as key mediators in the development and progression of hypertension. In this Review, we discuss our current understanding of the diverse roles of innate and adaptive immune cells in hypertension, highlighting key findings from human and rodent studies. We explore mechanisms by which these immune cells promote hypertensive pathophysiology, shedding light on their multifaceted involvement. In addition, we highlight advances in our understanding of autoimmunity, HIV and immune checkpoints that provide valuable insight into mechanisms of chronic and dysregulated inflammation in hypertension.
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Affiliation(s)
- Bianca A Nguyen
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Matthew R Alexander
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, USA
| | - David G Harrison
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN, USA.
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
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Zhao J, Lu N, Qu Y, Liu W, Zhong H, Tang N, Li J, Wang L, Xi D, He F. Calcium-sensing receptor-mediated macrophage polarization improves myocardial remodeling in spontaneously hypertensive rats. Exp Biol Med (Maywood) 2024; 249:10112. [PMID: 38715976 PMCID: PMC11075494 DOI: 10.3389/ebm.2024.10112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 11/13/2023] [Indexed: 06/04/2024] Open
Abstract
Chronic inflammation is a key element in the progression of essential hypertension (EH). Calcium plays a key role in inflammation, so its receptor, the calcium-sensing receptor (CaSR), is an essential mediator of the inflammatory process. Compelling evidence suggests that CaSR mediates inflammation in tissues and immune cells, where it mediates their activity and chemotaxis. Macrophages (Mφs) play a major role in the inflammatory response process. This study provided convincing evidence that R568, a positive regulator of CaSR, was effective in lowering blood pressure in spontaneously hypertensive rats (SHRs), improving cardiac function by alleviating cardiac hypertrophy and fibrosis. R568 can increase the content of CaSR and M2 macrophages (M2Mφs, exert an anti-inflammatory effect) in myocardial tissue, reduce M1 macrophages (M1Mφs), which have a pro-inflammatory effect in this process. In contrast, NPS2143, a negative state regulator of CaSR, exerted the opposite effect in all of the above experiments. Following this study, R568 increased CaSR content in SHR myocardial tissue, lowered blood pressure, promoted macrophages to M2Mφs and improved myocardial fibrosis, but interestingly, both M1Mφs and M2Mφs were increased in the peritoneal cavity of SHRs, the number of M2Mφs remained lower than M1Mφs. In vitro, R568 increased CaSR content in RAW264.7 cells (a macrophage cell line), regulating intracellular Ca2+ ([Ca2+]i) inhibited NOD-like receptor family protein 3 (NLRP3) inflammasome activation and ultimately prevented its conversion to M1Mφs. The results showed that a decrease in CaSR in hypertensive rats causes further development of hypertension and cardiac damage. EH myocardial remodeling can be improved by CaSR overexpression by suppressing NLRP3 inflammasome activation and macrophage polarization toward M1Mφs and increasing M2Mφs.
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Affiliation(s)
- Jiaqi Zhao
- Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Ning Lu
- School of Medicine, Tarim University, Alaer, Xinjiang, China
| | - Yuanyuan Qu
- Department of Respiratory Medicine, The First Affiliated Hospital of Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Wei Liu
- Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Hua Zhong
- Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Na Tang
- Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Jiayi Li
- Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Lamei Wang
- Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Dongmei Xi
- Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
| | - Fang He
- Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China
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Xiao K, Xv Z, Liu L, Yang B, Cao H, Wang J, Xv Y, Li Q, Hou Y, Feng F, Wang J, Feng H. Relationship between homocysteine and chronic total coronary occlusion: a cross-sectional study from southwest China. Cardiol Young 2024; 34:740-747. [PMID: 37811581 DOI: 10.1017/s1047951123003414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
BACKGROUND Chronic total coronary occlusion is among the most complex coronary artery diseases. Elevated homocysteine is a risk factor for coronary artery diseases. However, few studies have assessed the relationship between homocysteine and chronic total coronary occlusion. METHODS 1295 individuals from Southwest China were enrolled in the study. Chronic total coronary occlusion was defined as complete occlusion of coronary artery for more than three months. Homocysteine was divided into quartiles according to its level. Univariate and multivariate logistic regression models, receiver operating characteristic curves, and subgroup analysis were applied to assess the relationship between homocysteine and chronic total coronary occlusion. RESULTS Subjects in the higher homocysteine quartile had a higher rate of chronic total coronary occlusion (P < 0.001). After adjustment, the odds ratio for chronic total coronary occlusion in the highest quartile of homocysteine compared with the lowest was 1.918 (95% confidence interval 1.237-2.972). Homocysteine ≥ 15.2 μmol/L was considered an independent indicator of chronic total coronary occlusion (odds ratio 1.53, 95% confidence interval 1.05-2.23; P = 0.0265). The area under the receiver operating characteristic curve was 0.659 (95% confidence interval, 0.618-0.701; P < 0.001). Stronger associations were observed in elderly and in those with hypertension and diabetes. CONCLUSIONS Elevated homocysteine is significantly associated with chronic total coronary occlusion, particularly in elderly and those with hypertension and diabetes.
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Affiliation(s)
- Kaiyong Xiao
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, SC, China
| | - Zhe Xv
- Department of Pediatric Medicine, Guangyuan Central Hospital, Guangyuan, SC, China
| | - Liang Liu
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, SX, China
| | - Bin Yang
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, SX, China
| | - Huili Cao
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, SX, China
| | - Jianping Wang
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, SC, China
| | - Yuling Xv
- Sterilization Supply Center, Guangyuan Central Hospital, Guangyuan, SC, China
| | - Qingrui Li
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, SC, China
| | - Yulin Hou
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, SC, China
| | - Feifei Feng
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, SC, China
| | - Jie Wang
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, SC, China
| | - Hui Feng
- Medical Laboratory Center, Guangyuan Central Hospital, Guangyuan, SC, China
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Zhou Q, Yu M, Jin M, Zhang P, Qin G, Yao Y. Impact of free hypertension pharmacy program and social distancing policy on stroke: A longitudinal study. Front Public Health 2023; 11:1142299. [PMID: 37143973 PMCID: PMC10151749 DOI: 10.3389/fpubh.2023.1142299] [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: 02/03/2023] [Accepted: 03/28/2023] [Indexed: 05/06/2023] Open
Abstract
Background The estimated lifetime risk of stroke was the highest in East Asia worldwide, especially in China. Antihypertensive therapy can significantly reduce stroke mortality. However, blood pressure control is poor. Medication adherence is a barrier as patients' out-of-pocket costs have risen. We aimed to take advantage of a free hypertension pharmacy intervention and quantified the impact on stroke mortality. Methods A free pharmaceutical intervention program was implemented in Deqing, Zhejiang province in April 2018. Another non-pharmaceutical intervention, social distancing due to the pandemic of Coronavirus disease 2019 (COVID-19), was also key to affecting stroke mortality. We retrospectively collected the routine surveillance data of stroke deaths from Huzhou Municipal Center for Disease Prevention and Control in 2013-2020 and obtained within-city mobility data from Baidu Migration in 2019-2020, then we quantified the effects of both pharmaceutical intervention and social distancing using Serfling regression model. Results Compared to the predicted number, the actual number of stroke deaths was significantly lower by 10% (95% CI, 6-15%; p < 0.001) from April 2018 to December 2020 in Deqing. Specifically, there was a reduction of 19% (95% CI, 10-28%; p < 0.001) in 2018. Moreover, we observed a 5% (95% CI, -4 - 14%; p = 0.28) increase in stroke mortality due to the adverse effect of COVID-19 but it wasn't statistically significant. Conclusion Free hypertension pharmacy program has great potential to prevent considerable stroke deaths. In the future, the free supply of low-cost, essential medications that target patients with hypertension at increased risk of stroke could be taken into account in formulating public health policies and guiding allocations of health care resources.
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Affiliation(s)
- Qi Zhou
- Department of Biostatistics, School of Public Health and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Meihua Yu
- Huzhou Center for Disease Control and Prevention, Huzhou, Zhejiang, China
| | - Meihua Jin
- Huzhou Center for Disease Control and Prevention, Huzhou, Zhejiang, China
- *Correspondence: Meihua Jin,
| | - Peng Zhang
- Huzhou Center for Disease Control and Prevention, Huzhou, Zhejiang, China
| | - Guoyou Qin
- Department of Biostatistics, School of Public Health and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Ye Yao
- Department of Biostatistics, School of Public Health and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
- Ye Yao,
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Benson LN, Liu Y, Deck K, Mora C, Mu S. IFN- γ Contributes to the Immune Mechanisms of Hypertension. KIDNEY360 2022; 3:2164-2173. [PMID: 36591357 PMCID: PMC9802558 DOI: 10.34067/kid.0001292022] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 10/19/2022] [Indexed: 12/31/2022]
Abstract
Hypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For more than half a century, researchers have demonstrated that immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that proinflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension. Interferon gamma (IFN-γ), in particular, as an important cytokine that modulates immune responses, has been recently identified as a critical regulator of blood pressure by several groups, including us. In this review, we focus on exploring the role of IFN-γ in contributing to the pathogenesis of hypertension, outlining the various immune producers of this cytokine and described signaling mechanisms involved. We demonstrate a key role for IFN-γ in hypertension through global knockout studies and related downstream signaling pathways that IFN-γ production from CD8+ T cell (CD8T) in the kidney promoting CD8T-stimulated salt retention via renal tubule cells, thereby exacerbating hypertension. We discuss potential activators of these T cells described by the current literature and relay a novel hypothesis for activation.
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Affiliation(s)
- Lance N. Benson
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Yunmeng Liu
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Katherine Deck
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Christoph Mora
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Shengyu Mu
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Raubenheimer K, Liu AH, Koch H, Bosio E, Bondonno NP, Matthews V, Sim M, Blekkenhorst L, Woodman RJ, Murray K, Croft K, Neubauer O, Hodgson JM, Bondonno CP. Increased nitrate intake from beetroot juice does not alter soluble cellular adhesion molecules and circulating inflammatory cytokines in individuals with treated hypertension: a randomised, controlled trial. Food Funct 2022; 13:12353-12362. [PMID: 36367386 DOI: 10.1039/d2fo02403a] [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: 02/12/2025]
Abstract
Dietary nitrate, found predominantly in green leafy vegetables and other vegetables such as radish, celery, and beetroot, has been shown to beneficially modulate inflammatory processes and immune cell function in animals and healthy individuals. The impact of increased nitrate intake on soluble inflammatory mediators in individuals with hypertension is unclear. We assessed whether the daily consumption of dietary nitrate via beetroot juice for 1-week lowered levels of circulating inflammatory markers in men and women with treated hypertension. Twenty-seven male and female participants were recruited to a randomized, placebo-controlled, double-blind crossover trial. The effects of 1-week intake of nitrate-rich beetroot juice versus 1-week intake of nitrate-depleted beetroot juice (placebo) were investigated. Plasma concentrations of circulating soluble adhesion molecules (ICAM-1, VCAM-1, CD62E, CD62P), inflammatory cytokines (IL-1β, IL-6, IL-10, IL-12p70, TNF-α) and chemokines (IL-8, MCP-1) were measured by multiplex flow cytometric bead array in samples collected on day 7 of each intervention period. Other outcomes included alterations in nitrate metabolism assessed by measuring nitrate and nitrite concentrations in plasma, saliva, and urine. One week of beetroot juice did not alter levels of the soluble adhesion markers or cytokines assessed. A 7-fold increase in salivary nitrite, an 8-fold increase in salivary nitrate, a 3-fold increase in plasma nitrate and nitrite, and a 4-fold increase in urinary nitrate and nitrite compared to the placebo was observed (p < 0.001 for all comparisons). Increasing dietary nitrate consumption over 7 days is not effective in reducing soluble inflammatory mediators in individuals with treated hypertension. This trial was registered at anzctr.org.au as ACTRN 12613000116729.
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Affiliation(s)
- Kyle Raubenheimer
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
| | - Alex H Liu
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
- Medical School, University of Western Australia, Perth, Western Australia, Australia
| | - Henrietta Koch
- School of Biomedical Sciences, Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia
| | - Erika Bosio
- Medical School, University of Western Australia, Perth, Western Australia, Australia
- School of Biomedical Sciences, Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia
- Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia
| | - Nicola P Bondonno
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
- School of Biomedical Sciences, Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia
| | - Vance Matthews
- Dobney Hypertension Centre, Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia
| | - Marc Sim
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
- Medical School, University of Western Australia, Perth, Western Australia, Australia
| | - Lauren Blekkenhorst
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
| | - Richard J Woodman
- Flinders Centre for Epidemiology and Biostatistics, Flinders University, Adelaide, SA, Australia
| | - Kevin Murray
- School of Population and Global Health, University of Western Australia, Australia
| | - Kevin Croft
- School of Biomedical Sciences, Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia
| | - Oliver Neubauer
- Centre for Health Sciences and Medicine, Danube University Krems, Krems, Austria
- Research Platform Active Ageing, University of Vienna, Vienna, Austria
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Jonathan M Hodgson
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
- Medical School, University of Western Australia, Perth, Western Australia, Australia
| | - Catherine P Bondonno
- Nutrition & Health Innovation Research Institute, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
- Medical School, University of Western Australia, Perth, Western Australia, Australia
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11
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Huo M, Cao X, Zhang H, Lau CW, Hong H, Chen FM, Huang Y, Chawla A, Tian XY. Loss of myeloid Bmal1 exacerbates hypertensive vascular remodelling through interaction with STAT6 in mice. Cardiovasc Res 2022; 118:2859-2874. [PMID: 34726702 DOI: 10.1093/cvr/cvab336] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 09/07/2021] [Indexed: 01/11/2023] Open
Abstract
AIMS In addition to its involvement of inflammatory responses, limited information is available on the phenotype and behaviour of vascular macrophages during hypertensive vascular remodelling. Here, we aim at studying the contribution of BMAL1 to the pro-fibrotic macrophage phenotype in the vasculature during hypertension, which leads to enhanced vascular remodelling and promoted blood pressure increase. METHODS AND RESULTS Wild type Bmal1f/f and myeloid cell selective Bmal1 knockout Bmal1f/f; LysMCre/+ mice were infused with AngII for 4 weeks to induce hypertension. AngII-induced blood pressure increase, vascular media thickness and vascular dysfunction were enhanced in Bmal1f/f; LysMCre/+ mice, accompanied with a pro-fibrotic M2 phenotype of the vascular macrophages. Bmal1f/f; LysMCre/+ mice also have more up-regulations of MMP9 and MMP13 expression in the vascular wall, accompanied by enhanced collagen deposition after AngII infusion. Loss of Bmal1 in bone marrow-derived macrophages enhanced STAT6 activation induced by IL4, and the subsequent MMP13 up-regulation and activity. In macrophages, loss of Bmal1 enhanced the phosphorylation and nuclear translocation of STAT6 triggered by IL4, through possibly a direct interaction between BMAL1 and STAT6. To further determine whether IL4-induced signalling in macrophage contributes to enhanced vascular remodelling in hypertensive mice, we showed that deletion of myeloid IL4Rα in Il4raf/f; LysMCre/+ mice attenuated blood pressure increase and hypertensive vascular remodelling after AngII infusion. CONCLUSIONS Our results suggested a tonic effect of BMAL1 deletion on hypertensive vascular remodelling. BMAL1 might inhibit IL4-STAT6 signalling in macrophages through the interaction with STAT6 to reduce STAT6 activation and target gene transcription, especially MMP9 and MMP13, contributing to vascular remodelling.
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Affiliation(s)
- Mingyu Huo
- School of Biomedical Sciences, Faculty of Medicine, CUHK Shenzhen Research Institute, Heart and Vascular Institute, Rm208, LIBSB, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China
- Digestive Medicine Centre, The Seventh Affiliated Hospital of Sun Yat-sen University, Zhenyuan Rd, Guangming (New) Dist., Shenzhen, China, 518107
| | - Xiaoyun Cao
- School of Biomedical Sciences, Faculty of Medicine, CUHK Shenzhen Research Institute, Heart and Vascular Institute, Rm208, LIBSB, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China
| | - Hongsong Zhang
- School of Biomedical Sciences, Faculty of Medicine, CUHK Shenzhen Research Institute, Heart and Vascular Institute, Rm208, LIBSB, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Changle Rd, Qinhuai District, Nanjing, Jiangsu, China, 210029
| | - Chi Wai Lau
- School of Biomedical Sciences, Faculty of Medicine, CUHK Shenzhen Research Institute, Heart and Vascular Institute, Rm208, LIBSB, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China
| | - Huiling Hong
- School of Biomedical Sciences, Faculty of Medicine, CUHK Shenzhen Research Institute, Heart and Vascular Institute, Rm208, LIBSB, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China
| | - Francis M Chen
- School of Life Sciences, MMW 505, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China
| | - Yu Huang
- School of Biomedical Sciences, Faculty of Medicine, CUHK Shenzhen Research Institute, Heart and Vascular Institute, Rm208, LIBSB, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China
| | - Ajay Chawla
- Department of Physiology, Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA 94143-0795
| | - Xiao Yu Tian
- School of Biomedical Sciences, Faculty of Medicine, CUHK Shenzhen Research Institute, Heart and Vascular Institute, Rm208, LIBSB, Chinese University of Hong Kong, Shatin, NT. Hong Kong SAR, China
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12
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Frąk W, Wojtasińska A, Lisińska W, Młynarska E, Franczyk B, Rysz J. Pathophysiology of Cardiovascular Diseases: New Insights into Molecular Mechanisms of Atherosclerosis, Arterial Hypertension, and Coronary Artery Disease. Biomedicines 2022; 10:biomedicines10081938. [PMID: 36009488 PMCID: PMC9405799 DOI: 10.3390/biomedicines10081938] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) are disorders associated with the heart and circulatory system. Atherosclerosis is its major underlying cause. CVDs are chronic and can remain hidden for a long time. Moreover, CVDs are the leading cause of global morbidity and mortality, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of CVDs, focusing on coronary artery disease along with atherosclerosis as its major cause and arterial hypertension. We discuss the endothelium dysfunction, inflammatory factors, and oxidation associated with atherosclerosis. Mechanisms such as dysfunction of the endothelium and inflammation, which have been identified as critical pathways for development of coronary artery disease, have become easier to diagnose in recent years. Relatively recently, evidence has been found indicating that interactions of the molecular and cellular elements such as matrix metalloproteinases, elements of the immune system, and oxidative stress are involved in the pathophysiology of arterial hypertension. Many studies have revealed several important inflammatory and genetic risk factors associated with CVDs. However, further investigation is crucial to improve our knowledge of CVDs progression and, more importantly, accelerate basic research to improve our understanding of the mechanism of pathophysiology.
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13
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Su S, Chen R, Zhang S, Shu H, Luo J. Immune system changes in those with hypertension when infected with SARS-CoV-2. Cell Immunol 2022; 378:104562. [PMID: 35901625 PMCID: PMC9183242 DOI: 10.1016/j.cellimm.2022.104562] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 06/01/2022] [Accepted: 06/06/2022] [Indexed: 01/08/2023]
Abstract
The coronavirus disease 2019 (COVID-19) outbreak has become an evolving global health crisis. With an increasing incidence of primary hypertension, there is greater awareness of the relationship between primary hypertension and the immune system [including CD4+, CD8+ T cells, interleukin-17 (IL-17)/T regulatory cells (Treg) balance, macrophages, natural killer (NK) cells, neutrophils, B cells, and cytokines]. Hypertension is associated with an increased risk of various infections, post-infection complications, and increased mortality from severe infections. Despite ongoing reports on the epidemiological and clinical features of COVID-19, no articles have systematically addressed the role of primary hypertension in COVID-19 or how COVID-19 affects hypertension or specific treatment in these high-risk groups. Here, we synthesize recent advances in understanding the relationship between primary hypertension and COVID-19 and its underlying mechanisms and provide specific treatment guidelines for these high-risk groups.
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14
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Wu SC, Rau CS, Kuo PJ, Shih FY, Lin HP, Wu YC, Hsieh TM, Liu HT, Hsieh CH. Profiling the Expression of Circulating Acute-Phase Proteins, Cytokines, and Checkpoint Proteins in Patients with Severe Trauma: A Pilot Study. J Inflamm Res 2021; 14:3739-3753. [PMID: 34393495 PMCID: PMC8354739 DOI: 10.2147/jir.s324056] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/28/2021] [Indexed: 01/20/2023] Open
Abstract
Purpose Severe trauma may lead to the systemic release of inflammatory mediators into the circulation with profound acute-phase responses; however, the understanding of the expression of these mediators remains limited. This study aimed to characterize the alterations in the expression of circulating acute-phase proteins, cytokines, and checkpoint proteins in patients with severe trauma injuries. Patients and Methods The study population included trauma patients in the intensive care unit (ICU) with an injury severity score equal to or greater than 16 and who had used a ventilator for 48 hours. A total of 12 female and 28 male patients were recruited for the study; six patients died and 34 survived. Blood samples collected at acute stages were compared with those drawn at the subacute stage, the time when the patients were discharged from the ICU, or before the discharge of the patients from the hospital. Results The study identified that the expression of acute-phase proteins, such as alpha-1-acid glycoprotein and C-reactive protein, and cytokines, including granulocyte colony-stimulating factor, interleukin-6, and interleukin-1 receptor antagonist, was elevated in the circulation after severe trauma. In contrast, the levels of acute-phase proteins, such as alpha-2-macroglobulin, serum amyloid P, and von Willebrand factor, and cytokines, including interleukin-4 and interferon gamma-induced protein 10, were reduced. However, there were no significant differences in the expression of checkpoint proteins in the circulation. Conclusion The dysregulated proteins identified in this study may serve as potential therapeutic targets or biomarkers for treating patients with severe trauma. However, the related biological functions of these dysregulated factors require further investigation to validate their functions.
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Affiliation(s)
- Shao-Chun Wu
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Shyuan Rau
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pao-Jen Kuo
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Fu-Yuan Shih
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hui-Ping Lin
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Chan Wu
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ting-Min Hsieh
- Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hang-Tsung Liu
- Department of Trauma Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ching-Hua Hsieh
- Department of Plastic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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15
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Abstract
PURPOSE OF REVIEW Macrophages play an important role in regulating homeostasis, kidney injury, repair, and tissue fibrogenesis. The present review will discuss recent advances that explore the novel subsets and functions of macrophage in the pathogenesis of kidney damage and hypertension. RECENT FINDINGS Macrophages differentiate into a variety of subsets in microenvironment-dependent manner. Although the M1/M2 nomenclature is still applied in considering the pro-inflammatory versus anti-inflammatory effects of macrophages in kidney injury, novel, and accurate macrophage phenotypes are defined by flow cytometric markers and single-cell RNA signatures. Studies exploring the crosstalk between macrophages and other cells are rapidly advancing with the additional recognition of exosome trafficking between cells. Using murine conditional mutants, actions of macrophage can be defined more precisely than in bone marrow transfer models. Some studies revealed the opposing effects of the same protein in renal parenchymal cells and macrophages, highlighting a need for the development of cell-specific immune therapies for translation. SUMMARY Macrophage-targeted therapies hold potential for limiting kidney injury and hypertension. To realize this potential, future studies will be required to understand precise mechanisms in macrophage polarization, crosstalk, proliferation, and maturation in the setting of renal disease.
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16
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Son M, Oh S, Lee HS, Choi J, Lee BJ, Park JH, Park CH, Son KH, Byun K. Gamma-aminobutyric acid-salt attenuated high cholesterol/high salt diet induced hypertension in mice. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2021; 25:27-38. [PMID: 33361535 PMCID: PMC7756537 DOI: 10.4196/kjpp.2021.25.1.27] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 10/04/2020] [Accepted: 10/11/2020] [Indexed: 12/13/2022]
Abstract
Excessive salt intake induces hypertension, but several gamma-aminobutyric acid (GABA) supplements have been shown to reduce blood pressure. GABAsalt, a fermented salt by L. brevis BJ20 containing GABA was prepared through the post-fermentation with refined salt and the fermented GABA extract. We evaluated the effect of GABA-salt on hypertension in a high salt, high cholesterol diet induced mouse model. We analyzed type 1 macrophage (M1) polarization, the expression of M1 related cytokines, GABA receptor expression, endothelial cell (EC) dysfunction, vascular smooth muscle cell (VSMC) proliferation, and medial thicknesses in mice model. GABA-salt attenuated diet-induced blood pressure increases, M1 polarization, and TNF-α and inducible nitric oxide synthase (NOS) levels in mouse aortas, and in salt treated macrophages in vitro. Furthermore, GABA-salt induced higher GABAB receptor and endothelial NOS (eNOS) and eNOS phosphorylation levels than those observed in salt treated ECs. In addition, GABA-salt attenuated EC dysfunction by decreasing the levels of adhesion molecules (E-selectin, Intercellular Adhesion Molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) and of von Willebrand Factor and reduced EC death. GABA-salt also reduced diet-induced reductions in the levels of eNOS, phosphorylated eNOS, VSMC proliferation and medial thickening in mouse aortic tissues, and attenuated Endothelin-1 levels in salt treated VSMCs. In summary, GABA-salt reduced high salt, high cholesterol diet induced hypertension in our mouse model by reducing M1 polarization, EC dysfunction, and VSMC proliferation.
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Affiliation(s)
- Myeongjoo Son
- Department of Anatomy and Cell Biology, Gachon University College of Medicine, Incheon 21999, Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
| | - Hye Sun Lee
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
| | - Junwon Choi
- Department of Anatomy and Cell Biology, Gachon University College of Medicine, Incheon 21999, Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
| | - Bae-Jin Lee
- Marine Bioprocess Co., Ltd., Busan 46048, Korea
| | | | - Chul Hyun Park
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Korea
| | - Kyunghee Byun
- Department of Anatomy and Cell Biology, Gachon University College of Medicine, Incheon 21999, Korea
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
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17
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Peterson MR, Getiye Y, Bosch L, Sanders AJ, Smith AR, Haller S, Wilson K, Paul Thomas D, He G. A potential role of caspase recruitment domain family member 9 (Card9) in transverse aortic constriction-induced cardiac dysfunction, fibrosis, and hypertrophy. Hypertens Res 2020; 43:1375-1384. [PMID: 32647279 DOI: 10.1038/s41440-020-0507-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 05/29/2020] [Accepted: 06/11/2020] [Indexed: 12/24/2022]
Abstract
Macrophage- and monocyte-derived cytokines are elevated in the myocardium of pressure-overloaded hearts, where they play critical roles in pathological remodeling. Caspase recruitment domain family member 9 (CARD9) regulates macrophage cytokine secretion, but its role in a transverse aortic constriction (TAC) model of pressure overload has not been evaluated. To investigate whether CARD9 may serve as a valuable therapeutic target, wild-type (WT) and CARD9-knockout mice were subjected to 3 months of TAC, and then cardiac function, hypertrophy, and fibrosis were analyzed. The expression of protein markers of myocardial autophagy and nuclear factor kappa B signaling was also investigated. At 1 month after TAC, cardiomyocyte contractile dynamics were measured in a separate cohort to further assess contractility and diastolic function. In WT but not CARD9-/- mice, TAC resulted in severe cardiomyocyte contractile dysfunction at 1 month and functional decrements in fractional shortening at 3 months in vivo. Furthermore, CARD9-/- mice did not develop cardiac fibrosis or hypertrophy. CARD9-/- mice also had decreased protein expression of inhibitor of κB kinase-α/β, decreased phosphorylation of p65, and increased expression of protein markers of autophagy. These findings suggest that CARD9 plays a role in pathological remodeling and cardiac dysfunction in mouse hearts subjected to TAC and should be investigated further.
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Affiliation(s)
- Matthew R Peterson
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Yohannes Getiye
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Luiza Bosch
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Alyssa J Sanders
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Aspen R Smith
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Samantha Haller
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Kayla Wilson
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - D Paul Thomas
- Division of Kinesiology & Health, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA
| | - Guanglong He
- School of Pharmacy, University of Wyoming College of Health Sciences, Laramie, WY, 82071, USA.
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Saxton SN, Clark BJ, Withers SB, Eringa EC, Heagerty AM. Mechanistic Links Between Obesity, Diabetes, and Blood Pressure: Role of Perivascular Adipose Tissue. Physiol Rev 2019; 99:1701-1763. [PMID: 31339053 DOI: 10.1152/physrev.00034.2018] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Obesity is increasingly prevalent and is associated with substantial cardiovascular risk. Adipose tissue distribution and morphology play a key role in determining the degree of adverse effects, and a key factor in the disease process appears to be the inflammatory cell population in adipose tissue. Healthy adipose tissue secretes a number of vasoactive adipokines and anti-inflammatory cytokines, and changes to this secretory profile will contribute to pathogenesis in obesity. In this review, we discuss the links between adipokine dysregulation and the development of hypertension and diabetes and explore the potential for manipulating adipose tissue morphology and its immune cell population to improve cardiovascular health in obesity.
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Affiliation(s)
- Sophie N Saxton
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Ben J Clark
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Sarah B Withers
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Etto C Eringa
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
| | - Anthony M Heagerty
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; School of Environment and Life Sciences, University of Salford, Salford, United Kingdom; and Department of Physiology, VU University Medical Centre, Amsterdam, Netherlands
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19
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Li J, Sun M, Ye J, Li Y, Jin R, Zheng H, Liang F. The Mechanism of Acupuncture in Treating Essential Hypertension: A Narrative Review. Int J Hypertens 2019; 2019:8676490. [PMID: 30984420 PMCID: PMC6431462 DOI: 10.1155/2019/8676490] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 02/14/2019] [Indexed: 01/13/2023] Open
Abstract
Essential hypertension has a high incidence worldwide, and patients with essential hypertension endure a lifetime of medication, leading to a heavy economic burden on the patient's family and causing serious impacts on the patient's quality of life. Much evidence has demonstrated that acupuncture as an adjunctive therapy can lower blood pressure in patients with hypertension, but the mechanism of its action is unclear. This article reviews the research from 2000 to 2018 regarding the mechanism of acupuncture for hypertension, and we summarize the current knowledge about using acupuncture for hypertension. We found that the mechanism whereby acupuncture lowers blood pressure is related to the regulation of renin-angiotensin-aldosterone system, vascular endothelium, oxidative stress, neuroendocrine system, and so on. Besides, there may be cross-talk between multiple systems and multiple targets. We also investigate the influence factors of acupuncture for hypertension. These results may provide evidence and research ideas for the treatment of hypertension via acupuncture.
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Affiliation(s)
- Juan Li
- College of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Mingsheng Sun
- College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Jing Ye
- College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Yuxi Li
- College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Rongjiang Jin
- College of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Hui Zheng
- College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
| | - Fanrong Liang
- College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
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20
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Zhang Y, Ding X, Dai H, Peng W, Guo N, Zhang Y, Zhou Q, Chen X. SB-216763, a GSK-3β inhibitor, protects against aldosterone-induced cardiac, and renal injury by activating autophagy. J Cell Biochem 2018; 119:5934-5943. [PMID: 29600538 PMCID: PMC6001754 DOI: 10.1002/jcb.26788] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 02/12/2018] [Indexed: 12/12/2022]
Abstract
Cardiovascular and renal inflammation induced by Aldosterone (Aldo) plays a pivotal role in the pathogenesis of hypertension and renal fibrosis. GSK-3β contributes to inflammatory cardiovascular and renal diseases, but its role in Aldo-induced hypertension, and renal damage is not clear. In the present study, rats were treated with Aldo combined with SB-216763 (a GSK-3β inhibitor) for 4 weeks. Hemodynamic, cardiac, and renal parameters were assayed at the indicated time. Here we found that rats treated with Aldo presented cardiac and renal hypertrophy and dysfunction. Cardiac and renal expression levels of molecular markers attesting inflammation and fibrosis were increased by Aldo infusion, whereas the treatment of SB-216763 reversed these alterations. SB-216763 suppressed cardiac and renal inflammatory cytokines levels (TNF-a, IL-1β, and MCP-1). Meanwhile, SB-216763 increased the protein levels of LC3-II in the cardiorenal tissues as well as p62 degradation, indicating that SB-216763 induced autophagy activation in cardiac, and renal tissues. Importantly, inhibition of autophagy by 3-MA attenuated the role of SB-216763 in inhibiting perivascular fibrosis, and tubulointerstitial injury. These data suggest that SB-216763 protected against Aldo-induced cardiac and renal injury by activating autophagy, and might be a therapeutic option for salt-sensitive hypertension and renal fibrosis.
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Affiliation(s)
- Yi‐De Zhang
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongJiangsuChina
| | - Xiao‐Jun Ding
- Department of CardiologyAffiliated Danyang People's Hospital of Nantong UniversityDanyangChina
| | - Hou‐Yong Dai
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongJiangsuChina
| | - Wei‐Sheng Peng
- Department of NephrologyAffiliated Xiangya Hospital of Central South UniversityChangshaHunanChina
| | - Nai‐Feng Guo
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongJiangsuChina
| | - Yuan Zhang
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongJiangsuChina
| | - Qiao‐Ling Zhou
- Department of NephrologyAffiliated Xiangya Hospital of Central South UniversityChangshaHunanChina
| | - Xiao‐Lan Chen
- Department of NephrologyAffiliated Hospital of Nantong UniversityNantongJiangsuChina
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21
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Abstract
The link between inappropriate salt retention in the kidney and hypertension is well recognized. However, growing evidence suggests that the immune system can play surprising roles in sodium homeostasis, such that the study of inflammatory cells and their secreted effectors has provided important insights into salt sensitivity. As part of the innate immune system, myeloid cells have diverse roles in blood pressure regulation, ranging from prohypertensive actions in the kidney, vasculature, and brain, to effects in the skin that attenuate blood pressure elevation. In parallel, T lymphocyte subsets, as key constituents of the adaptive immune compartment, have variable effects on renal sodium handling and the hypertensive response, accruing from the functions of the cytokines that they produce. Conversely, salt can directly modulate the phenotypes of myeloid and T cells, illustrating bidirectional regulatory mechanisms through which sodium and the immune system coordinately impact blood pressure. This review details the complex interplay between myeloid cells, T cells, and salt in the pathogenesis of essential hypertension.
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Affiliation(s)
- A Justin Rucker
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA; .,Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, USA
| | - Nathan P Rudemiller
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA; .,Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, USA
| | - Steven D Crowley
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA; .,Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, USA
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22
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The role of macrophages in hypertension and its complications. Pflugers Arch 2017; 469:419-430. [PMID: 28251313 DOI: 10.1007/s00424-017-1950-x] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 02/01/2017] [Accepted: 02/06/2017] [Indexed: 12/17/2022]
Abstract
Circulating monocytes and tissue macrophages play complex roles in the pathogenesis of hypertension, a highly prevalent disease associated with catastrophic cardiovascular morbidity. In the vasculature and kidney, macrophage-derived reactive oxygen species (ROS) and inflammatory cytokines induce endothelial and epithelial dysfunction, respectively, resulting in vascular oxidative stress and impairment of sodium excretion. By contrast, VEGF-C-expressing macrophages in the skin can facilitate the removal of excess interstitial stores of sodium by stimulating lymphangiogenesis. Inappropriate activation of the renin-angiotensin system (RAS) contributes to essential hypertension in a majority of patients, and macrophages express the type 1 (AT1) receptor for angiotensin II (Ang II). While proinflammatory macrophages clearly contribute to RAS-dependent hypertension, activation of the AT1 receptor directly on macrophages suppresses their M1 polarization and limits tubular and interstitial damage to the kidney during hypertension. Thus, stimulating the macrophage AT1 receptor ameliorates the target organ damage and immune stimulation provoked by AT1 receptor activation in intrinsic renal and vascular cells. The proinflammatory cytokines TNF-α and IL-1β produced by M1 macrophages drive blood pressure elevation and consequent target organ damage. However, additional studies are needed to identify the tissues in which these cytokines act and the signaling pathways they stimulate during hypertension. Moreover, identifying the precise myeloid cell subsets that contribute to hypertension should guide the development of more precise immunomodulatory therapies for patients with persistent blood pressure elevation and progressive end-organ injury.
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23
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Rudemiller NP, Crowley SD. Interactions Between the Immune and the Renin-Angiotensin Systems in Hypertension. Hypertension 2016; 68:289-96. [PMID: 27354427 PMCID: PMC4945449 DOI: 10.1161/hypertensionaha.116.06591] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Nathan P Rudemiller
- From the Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, NC
| | - Steven D Crowley
- From the Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, Durham, NC.
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24
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Zhang Y, Peng W, Ao X, Dai H, Yuan L, Huang X, Zhou Q. TAK-242, a Toll-Like Receptor 4 Antagonist, Protects against Aldosterone-Induced Cardiac and Renal Injury. PLoS One 2015; 10:e0142456. [PMID: 26556241 PMCID: PMC4640881 DOI: 10.1371/journal.pone.0142456] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 10/20/2015] [Indexed: 12/27/2022] Open
Abstract
Cardiovascular and renal inflammation induced by Aldosterone (Aldo) plays an important role in the pathogenesis of hypertension and renal fibrosis. Toll-like receptor 4 (TLR4) signaling contributes to inflammatory cardiovascular and renal diseases, but its role in Aldo-induced hypertension and renal damage is not clear. In the current study, rats were treated with Aldo-salt combined with TAK-242 (a TLR4 signaling antagonist) for 4 weeks. Hemodynamic, cardiac and renal parameters were assayed at the indicated time. We found that Aldo-salt–treated rats present cardiac and renal hypertrophy and dysfunction. Cardiac and renal expression levels of TLR4 as well as levels of molecular markers attesting inflammation and fibrosis are increased by Aldo infusion, whereas the treatment of TAK-242 reverses these alterations. TAK-242 suppresses cardiac and renal inflammatory cytokines levels (TNF-a, IL-1β and MCP-1). Furthermore, TAK-242 inhibits hypertension, cardiac and renal fibrosis, and also attenuates the Aldo-induced Epithelial-Mesenchymal Transition (EMT). In experimental hyperaldosteronism, upregulation of TLR4 is correlated with cardiac and renal fibrosis and dysfunction, and a TLR4 signaling antagonist, TAK-242, can reverse these alterations. TAK-242 may be a therapeutic option for salt-sensitive hypertension and renal fibrosis.
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Affiliation(s)
- Yide Zhang
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Weisheng Peng
- Department of Nephrology, Affiliated Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiang Ao
- Department of Nephrology, Affiliated Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Houyong Dai
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Li Yuan
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Xinzhong Huang
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Qiaoling Zhou
- Department of Nephrology, Affiliated Xiangya Hospital of Central South University, Changsha, Hunan, China
- * E-mail:
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25
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Peltsch H, Khurana S, Byrne CJ, Nguyen P, Khaper N, Kumar A, Tai TC. Cardiac phenylethanolamine N-methyltransferase: localization and regulation of gene expression in the spontaneously hypertensive rat. Can J Physiol Pharmacol 2015; 94:363-72. [PMID: 26761434 DOI: 10.1139/cjpp-2015-0303] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Phenylethanolamine N-methyltransferase (PNMT) is the terminal enzyme in the catecholamine biosynthetic pathway responsible for adrenaline biosynthesis. Adrenaline is involved in the sympathetic control of blood pressure; it augments cardiac function by increasing stroke volume and cardiac output. Genetic mapping studies have linked the PNMT gene to hypertension. This study examined the expression of cardiac PNMT and changes in its transcriptional regulators in the spontaneously hypertensive (SHR) and wild type Wistar-Kyoto (WKY) rats. SHR exhibit elevated levels of corticosterone, and lower levels of the cytokine IL-1β, revealing systemic differences between SHR and WKY. PNMT mRNA was significantly increased in all chambers of the heart in the SHR, with the greatest increase in the right atrium. Transcriptional regulators of the PNMT promoter show elevated expression of Egr-1, Sp1, AP-2, and GR mRNA in all chambers of the SHR heart, while protein levels of Sp1, Egr-1, and GR were elevated only in the right atrium. Interestingly, only AP-2 protein-DNA binding was increased, suggesting it may be a key regulator of cardiac PNMT in SHR. This study provides the first insights into the molecular mechanisms involved in the dysregulation of cardiac PNMT in a genetic model of hypertension.
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Affiliation(s)
- Heather Peltsch
- a Department of Biology, Laurentian University, Sudbury, ON, Canada
| | - Sandhya Khurana
- e Medical Sciences Division, Northern Ontario School of Medicine, East Campus, 935 Ramsey Lake Road, Sudbury, ON P3E 2C6, Canada
| | - Collin J Byrne
- a Department of Biology, Laurentian University, Sudbury, ON, Canada
| | - Phong Nguyen
- a Department of Biology, Laurentian University, Sudbury, ON, Canada
| | - Neelam Khaper
- d Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, ON, Canada
| | - Aseem Kumar
- b Department of Chemistry and Biochemistry, Laurentian University, Sudbury, ON, Canada.,c Biomolecular Sciences, Laurentian University, Sudbury, ON, Canada
| | - T C Tai
- a Department of Biology, Laurentian University, Sudbury, ON, Canada.,b Department of Chemistry and Biochemistry, Laurentian University, Sudbury, ON, Canada.,c Biomolecular Sciences, Laurentian University, Sudbury, ON, Canada.,e Medical Sciences Division, Northern Ontario School of Medicine, East Campus, 935 Ramsey Lake Road, Sudbury, ON P3E 2C6, Canada
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26
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Tayebati SK, Tomassoni D, Di Cesare Mannelli L, Amenta F. Effect of treatment with the antioxidant alpha-lipoic (thioctic) acid on heart and kidney microvasculature in spontaneously hypertensive rats. Clin Exp Hypertens 2015. [PMID: 26207883 DOI: 10.3109/10641963.2015.1047950] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Endothelial cells represent an important vascular site of signaling and development of damage during ischemia, inflammation and other pathological conditions. Excessive reactive oxygen species production causes pathological activation of endothelium including exposure of cell to adhesion molecules. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) are members of the immunoglobulin super-family which are present on the surface of endothelial cells. These molecules represent important markers of endothelial inflammation. The present study was designed to investigate, with immunochemical and immunohistochemical techniques, the effect of treatment with (+/-)-alpha lipoic (thioctic) acid and its enantiomers on heart and kidney endothelium in spontaneously hypertensive rats (SHR). Arterial hypertension is accompanied by an increased oxidative stress status in the heart characterized by thiobarbituric acid reactive substances (TBARS) and nucleic acid oxidation increase. The higher oxidative stress also modifies adhesion molecules expression. In the heart VCAM-1, which was higher than ICAM-1 and PECAM-1, was increased in SHR. ICAM-1, VCAM-1 and PECAM-1 expression was significantly greater in the renal endothelium of SHR. (+/-)-Alpha lipoic acid and (+)-alpha lipoic acid treatment significantly decreased TBARS levels, the nucleic acid oxidation and prevented adhesion molecules expression in cardiac and renal vascular endothelium. These data suggest that endothelial molecules may be used for studying the mechanisms of vascular injury on target organs of hypertension. The effects observed after treatment with (+)-alpha lipoic acid could open new perspectives for countering heart and kidney microvascular injury which represent a common feature in hypertensive end-organs damage.
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Affiliation(s)
| | - Daniele Tomassoni
- b School of Bioscience and Veterinary Medicine, University of Camerino , Camerino , Italy, and
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27
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Yu AP, Tam BT, Yau WY, Chan KS, Yu SS, Chung TL, Siu PM. Association of endothelin-1 and matrix metallopeptidase-9 with metabolic syndrome in middle-aged and older adults. Diabetol Metab Syndr 2015; 7:111. [PMID: 26692905 PMCID: PMC4676096 DOI: 10.1186/s13098-015-0108-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 11/25/2015] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) contains a cluster of cardiovascular risk factors. People with MetS are more susceptible to cardiovascular disease, diabetes mellitus, and cancer. Endothelin-1 (ET-1) and matrix metallopeptidase-9 (MMP-9) have been implicated in the development of cardiovascular diseases, diabetes mellitus and cancers. This cross-sectional study aimed to examine the association of ET-1 and MMP-9 with MetS in middle-aged and older Hong Kong Chinese adults. METHODS 149 adults aged 50 to 92 (n = 75 for non-MetS group and n = 74 for MetS group) were examined. All subjects were screened for MetS according to the diagnostic guideline of the United States National Cholesterol Education Program (NCEP) Expert Panel Adult Treatment Panel (ATP) III criteria. Serum levels of ET-1 and MMP-9 were measured. Independent t test was used to detect differences between non-MetS and MetS groups and between subjects with or without certain metabolic abnormality. The association of the serum concentration of MMP-9 and ET-1 with MetS parameters were examined by Pearson's correlation analysis. RESULTS Serum level of ET-1 is higher in MetS-positive subjects and in subjects with high blood pressure, elevated fasting blood glucose, and central obesity. The serum concentration of MMP-9 is higher in subjects positively diagnosed with MetS and subjects with high blood pressure, elevated fasting blood glucose, low blood high-density lipoprotein-cholesterol (HDL-C), high blood triglycerides, and central obesity. Correlation analyses revealed that serum concentration of ET-1 is positively correlated to systolic blood pressure, waist circumference, fasting blood glucose, and age whereas it is negatively correlated to HDL-C. MMP-9 is positively correlated to systolic blood pressure, waist circumference, fasting blood glucose, and age whereas it is negatively correlated to HDL-C. CONCLUSION Serum ET-1 is higher in subjects with hypertension, hyperglycemia, central obesity or MetS. Serum MMP-9 is higher in subjects diagnosed with MetS or having either one of the MetS parameters. Both circulating levels of ET-1 and MMP-9 are correlated to systolic blood pressure, waist circumference, fasting blood glucose, HDL-C, and age. Further research is needed to fully dissect the role of ET-1 and MMP-9 in the development of cancers, diabetes and cardiovascular disease in relation to MetS.
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Affiliation(s)
- A. P. Yu
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - B. T. Tam
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - W. Y. Yau
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - K. S. Chan
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - S. S. Yu
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - T. L. Chung
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
| | - P. M. Siu
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China
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Helbing T, Olivier C, Bode C, Moser M, Diehl P. Role of microparticles in endothelial dysfunction and arterial hypertension. World J Cardiol 2014; 6:1135-1139. [PMID: 25429325 PMCID: PMC4244610 DOI: 10.4330/wjc.v6.i11.1135] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 08/29/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Microparticles are small cell vesicles that can be released by almost all eukaryotic cells during cellular stress and cell activation. Within the last 1-2 decades it has been shown that microparticles are useful blood surrogate markers for different pathological conditions, such as vascular inflammation, coagulation and tumour diseases. Several studies have investigated the abundance of microparticles of different cellular origins in multiple cardiovascular diseases. It thereby has been shown that microparticles released by platelets, leukocytes and endothelial cells can be found in conditions of endothelial dysfunction, acute and chronic vascular inflammation and hypercoagulation. In addition to their function as surrogate markers, several studies indicate that circulating microparticles can fuse with distinct target cells, such as endothelial cells or leukocyte, and thereby deliver cellular components of their parental cells to the target cells. Hence, microparticles are a novel entity of circulating, paracrine, biological vectors which can influence the phenotype, the function and presumably even the transcriptome of their target cells.
This review article aims to give a brief overview about the microparticle biology with a focus on endothelial activation and arterial hypertension. More detailed information about the role of microparticles in pathophysiology and disease can be found in already published work.
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29
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Mirhafez SR, Mohebati M, Feiz Disfani M, Saberi Karimian M, Ebrahimi M, Avan A, Eslami S, Pasdar A, Rooki H, Esmaeili H, Ferns GA, Ghayour-Mobarhan M. An imbalance in serum concentrations of inflammatory and anti-inflammatory cytokines in hypertension. JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION : JASH 2014; 8:614-623. [PMID: 25224864 DOI: 10.1016/j.jash.2014.05.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 05/13/2014] [Accepted: 05/14/2014] [Indexed: 01/19/2023]
Abstract
Hypertension is an important risk factor for cardiovascular disease and there is increasing evidence that inflammation and abnormal immune responses are involved in the pathogenesis of hypertension. However, the data on the association between specific cytokine concentrations and hypertension are inconsistent. We have evaluated the association between 12 cytokines/growth factors and the presence of different degrees of hypertension, comparing these concentrations to values in a healthy group of subjects. The concentrations of interleukin (IL)-1α, -1β, -2, -4, -6, -8, -10, tumor necrosis factor (TNF-α), interferon-γ (IFN-γ), monocyte chemoattractant protein (MCP-1), epidermal growth factor, and vascular endothelial growth factor were measured in 155 hypertensive patients and 148 healthy subjects, using EV-3513 cytokine biochip arrays, a competitive chemiluminescence immunoassay. Univariate and multivariate analyses were used to evaluate the association of specific cytokines and growth factors with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Hypertensive subjects had higher serum concentrations of IL-1α, -2, -8, vascular endothelial growth factor, IFN-γ, TNF-α, MCP-1, and epidermal growth factor; and lower concentrations of anti-inflammatory cytokine, IL-10 (P < .05), compared with the healthy individuals. The serum concentrations of IL-4, -6, and -1β did not differ between the hypertensive subjects and control group. Univariate and multivariate analyses revealed that IL-1α and IFN-γ were independent predictors of a high SBP, while IFN-γ, IL-1α, TNF-α, and MCP-1 remained statistically significant for DBP after correction for age, gender, Body mass index, smoking, fasting blood glucose, and triglycerides. There was a significant association between the concentrations of several cytokines and hypertension. These associations may either be related to common underlying factors that cause hypertension and may also be proinflammatory or because these inflammatory cytokines might directly be involved in the etiology of hypertension.
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Affiliation(s)
- Seyed Reza Mirhafez
- Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Mohebati
- Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahboobeh Feiz Disfani
- Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Saberi Karimian
- Student Research Committee, Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Ebrahimi
- Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Department of New Sciences & Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Oncology, VU University Medical Center, Amsterdam, Amsterdam, The Netherlands
| | - Saied Eslami
- Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Informatics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Pasdar
- Department of New Sciences & Technology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Division of Applied Medicine, Medical School, University of Aberdeen, Foresterhill, Aberdeen, UK
| | - Hassan Rooki
- Biochemistry of Nutrition Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Habibollah Esmaeili
- Biochemistry of Nutrition Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Falmer, Brighton, Sussex, UK
| | - Majid Ghayour-Mobarhan
- Cardiovascular Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Biochemistry of Nutrition Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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30
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The association between smoking quantity and hypertension mediated by inflammation in Chinese current smokers. J Hypertens 2014; 31:1798-805. [PMID: 24036901 DOI: 10.1097/hjh.0b013e328362c21a] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Previous studies indicated that cigarette smokers were more likely to develop hypertension, and both smoking and hypertension were associated with inflammation. Whether inflammation mediates the relationship of them is unclear. This study aims to examine whether inflammation mediates the association between smoking and hypertension. METHODS Nine hundred and eighty-four Chinese current smokers from a community-based chronic diseases survey in Guangzhou and Zhuhai were interviewed about sociodemographics, smoking, chronic conditions, and other health-related variables. Hypertension was defined according to 2007 European Society of Hypertension and European Society of Cardiology (ESH-ESC) Practice Guidelines. Inflammatory markers including C-reactive protein (CRP), interleukin (IL)-6, IL-1β, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and vascular cell adhesion molecule-1 (VCAM-1) were measured by flow cytometry. Logistic regressions were performed to assess the mediation of inflammation on the relationship between smoking quantity and hypertension. RESULTS We observed a positive association between smoking quantity and hypertension (P<0.05). After controlling for potential confounders, daily cigarette consumption was significantly associated with higher level of CRP and VCAM-1 and lower level of TNF-α among six measured inflammatory markers, and the current smokers with hypertension had significantly higher level of MCP-1 and CRP than those smokers who were normotensive. Furthermore, the association between smoking quantity and hypertension was mediated by CRP, which accounted for 58.59% of the estimated causal effect of smoking on hypertension. CONCLUSION We have confirmed previous observations that smoking quantity was positively associated with hypertension, and the results of our study suggested that the association between smoking and hypertension was probably mediated by CRP.
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31
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Leong XF, Ng CY, Badiah B, Das S. Association between hypertension and periodontitis: possible mechanisms. ScientificWorldJournal 2014; 2014:768237. [PMID: 24526921 PMCID: PMC3910336 DOI: 10.1155/2014/768237] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 12/15/2013] [Indexed: 02/07/2023] Open
Abstract
This review is to examine the current literatures on the relationship between periodontitis and hypertension as well as to explore the possible biological pathways underlying the linkage between these health conditions. Hypertension is one of the major risk factors for cardiovascular diseases. Oxidative stress and endothelial dysfunction are among the critical components in the development of hypertension. Inflammation has received much attention recently and may contribute to a pivotal role in hypertension. Periodontitis, a chronic low-grade inflammation of gingival tissue, has been linked to endothelial dysfunction, with blood pressure elevation and increased mortality risk in hypertensive patients. Inflammatory biomarkers are increased in hypertensive patients with periodontitis. Over the years, various researches have been performed to evaluate the involvement of periodontitis in the initiation and progression of hypertension. Many cross-sectional studies documented an association between hypertension and periodontitis. However, more well-designed prospective population trials need to be carried out to ascertain the role of periodontitis in hypertension.
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Affiliation(s)
- Xin-Fang Leong
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
- Department of Clinical Oral Biology, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
| | - Chun-Yi Ng
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
| | - Baharin Badiah
- Department of Periodontology, Faculty of Dentistry, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
| | - Srijit Das
- Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
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Javeshghani D, Barhoumi T, Idris-Khodja N, Paradis P, Schiffrin EL. Reduced Macrophage-Dependent Inflammation Improves Endothelin-1–Induced Vascular Injury. Hypertension 2013; 62:112-7. [DOI: 10.1161/hypertensionaha.113.01298] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Transgenic mice with endothelium-specific endothelin-1 (ET-1) overexpression exhibit endothelial dysfunction and vascular remodeling, oxidative stress, and inflammation. We previously observed that monocytes/macrophages play a role in angiotensin II, aldosterone, and deoxycorticosterone acetate/salt-induced vascular remodeling, oxidative stress, and inflammation using a model with reduced monocytes/macrophages, the osteopetrotic (Op) mouse, which has a mutation in the macrophage colony stimulating factor (
Csf1
) gene. However, it is unknown whether monocytes/macrophages are implicated in adverse vascular effects of ET-1. We hypothesized that reduction in monocytes/macrophages would blunt ET-1–induced vascular injury. We performed a study on 4- to 6-month-old male mice with endothelium-specific ET-1 overexpression (eET-1), reduction in CSF1 (
Csf1
Op/+
), or both (eET-1/
Csf1
Op/+
), and their wild-type littermate control mice. There was no difference in systolic blood pressure between groups. Endothelial function and vascular structure were determined on a pressurized myograph. Endothelium-dependent relaxation in response to acetylcholine was similar in eET-1 and eET-1/
Csf1
Op/+
mice. Media:lumen ratio and media cross-sectional area were ≈1.5-fold greater in eET-1 than in wild-type mice (
P
<0.05), which was not observed in mice deficient in CSF1. ET-1–induced oxidative stress measured by dihydroethidium staining (
P
<0.05) and NADPH oxidase activity assessed with lucigenin chemiluminescence (
P
<0.05) were blunted by CSF1 deficiency. ET-1 caused a 2.5-fold increase in monocyte/macrophage infiltration compared with wild-type mice (
P
<0.001), which was blunted in the mice deficient in CSF1. Reduction of monocyte/macrophage-dependent inflammation in mice overexpressing ET-1 in endothelium results in reduced vascular remodeling and oxidative stress, providing evidence for a role of monocytes/macrophages and innate immunity in ET-1–induced vascular injury.
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Affiliation(s)
- Danesh Javeshghani
- From the Lady Davis Institute for Medical Research (D.J., T.B., N.I.-K., P.P., E.L.S.), Department of Medicine (E.L.S.), Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and Jahrom University of Medical Sciences, Jahrom, Islamic Republic of Iran (D.J.)
| | - Tlili Barhoumi
- From the Lady Davis Institute for Medical Research (D.J., T.B., N.I.-K., P.P., E.L.S.), Department of Medicine (E.L.S.), Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and Jahrom University of Medical Sciences, Jahrom, Islamic Republic of Iran (D.J.)
| | - Nourredine Idris-Khodja
- From the Lady Davis Institute for Medical Research (D.J., T.B., N.I.-K., P.P., E.L.S.), Department of Medicine (E.L.S.), Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and Jahrom University of Medical Sciences, Jahrom, Islamic Republic of Iran (D.J.)
| | - Pierre Paradis
- From the Lady Davis Institute for Medical Research (D.J., T.B., N.I.-K., P.P., E.L.S.), Department of Medicine (E.L.S.), Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and Jahrom University of Medical Sciences, Jahrom, Islamic Republic of Iran (D.J.)
| | - Ernesto L. Schiffrin
- From the Lady Davis Institute for Medical Research (D.J., T.B., N.I.-K., P.P., E.L.S.), Department of Medicine (E.L.S.), Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and Jahrom University of Medical Sciences, Jahrom, Islamic Republic of Iran (D.J.)
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Zhou J, Zhang X, Zhang H, Jia Y, Liu Y, Tang Y, Li X. Use of data mining to determine changes in the gene expression profiles of rat embryos following prenatal exposure to inflammatory stimulants. Mol Med Rep 2013; 8:95-102. [PMID: 23722200 DOI: 10.3892/mmr.2013.1498] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 05/16/2013] [Indexed: 11/06/2022] Open
Abstract
Numerous clinical epidemiology and laboratory studies have demonstrated a close association between inflammation or immunity and the occurrence of hypertension. Our group has previously shown that upon intraperitoneal injection of lipopolysaccharide (LPS) or zymosan (Zym) into pregnant rats, the offspring of the experimental group exhibited higher blood pressure levels compared with the control group, and these may be associated with the effects of an accumulation of gene expression changes on female rats during pregnancy. The present study used the Affymetrix GeneChip® Rat Genome 230 2.0 Array to examine gene expression profile changes in the embryos of experimental pregnant rats intraperitoneally injected with LPS or Zym vs. the untreated controls. We discovered that genes associated with DNA replication and mRNA processing were significantly upregulated by the stimuli from analysis using GenMAPP. By contrast, genes involved in the calcium regulatory pathway in cardiac myocytes and the signaling pathway in smooth muscle contraction and relaxation were the most downregulated. Results of the microarray analysis showed that immuno-inflammatory stimuli during pregnancy affected the gene expression profiles of the embryos. These changes in gene expression may affect the developmental and metabolic status of the offspring, thereby increasing their susceptibility to hypertension and obesity.
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Affiliation(s)
- Jianzhi Zhou
- Institute of Materia Medical, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China
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Tung D, Ciallella J, Cheung PH, Saha S. Novel Anti-Inflammatory Effects of Doxazosin in Rodent Models of Inflammation. Pharmacology 2013; 91:29-34. [DOI: 10.1159/000343762] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Accepted: 09/24/2012] [Indexed: 12/22/2022]
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Blyszczuk P, Behnke S, Lüscher TF, Eriksson U, Kania G. GM-CSF promotes inflammatory dendritic cell formation but does not contribute to disease progression in experimental autoimmune myocarditis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2012; 1833:934-44. [PMID: 23103516 DOI: 10.1016/j.bbamcr.2012.10.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 10/03/2012] [Accepted: 10/04/2012] [Indexed: 11/29/2022]
Abstract
BACKGROUND Granulocyte macrophage-colony stimulating factor (GM-CSF) is critically required for the induction of experimental autoimmune myocarditis (EAM), a model of post-inflammatory dilated cardiomyopathy. Its specific role in the progression of myocarditis into end stage heart failure is not known. METHODS AND RESULTS BALB/c mice were immunized with myosin peptide and complete Freund's adjuvant at days 0 and 7. Heart-infiltrating inflammatory CD133(+) progenitors were isolated from inflamed hearts at the peak of inflammation (day 21). In the presence of GM-CSF, inflammatory CD133(+) progenitors up-regulated integrin, alpha X (CD11c), class II major histocompatibility complex, CD80 and CD86 co-stimulatory molecules reflecting an inflammatory dendritic cell (DC) phenotype. Inflammatory DCs stimulated antigen-specific CD4(+) T cell proliferation and induced myocarditis after myosin peptide loading and adoptive transfer in healthy mice. Moreover, GM-CSF treatment of mice after the peak of disease, between days 21 and 29 of EAM, transiently increased accumulation of inflammatory DCs in the myocardium. Importantly, bone marrow-derived CD11b(+) monocytes, rather than inflammatory CD133(+) progenitors represent the dominant cellular source of heart-infiltrating inflammatory DCs in EAM. In contrast, GM-CSF treatment neither affected numbers of heart-infiltrating CD45(+) and CD3(+) T cells nor the development of post-inflammatory fibrosis. CONCLUSIONS GM-CSF treatment promotes formation of inflammatory DCs in EAM. In contrast to the active roles of GM-CSF and DCs in EAM induction, GM-CSF-induced inflammatory DCs neither prevent resolution of active inflammation, nor contribute to post-inflammatory cardiac remodelling. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.
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Abstract
Chemokines are best known for their classic leukocyte chemotactic activity, which is critical for directing the immune response to sites of infection and injury. However, recent studies have suggested that at least some chemokines may also interfere with infectious agents directly. Antimicrobial chemokines tend to contain amphipathic alpha helical secondary structure, and broad-spectrum activity against both Gram-positive and Gram negative bacteria, as well as fungi. Conversely, several bacteria have been identified that possess mechanisms for specifically blocking the antimicrobial activities of chemokines. Although the precise mechanisms by which chemokines and microbes disarm one another in vitro remain unknown, there is now emerging evidence in vivo that such interactions may be biologically significant. More research will be needed to determine whether chemokines with direct antimicrobial activity may be translated into a novel class of antibiotics.
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Affiliation(s)
- Sunny C. Yung
- Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesda, MD, USA
| | - Philip M. Murphy
- Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesda, MD, USA
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Dietary salt intake is related to inflammation and albuminuria in primary hypertensive patients. Eur J Clin Nutr 2012; 66:1214-8. [PMID: 22909578 DOI: 10.1038/ejcn.2012.110] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND/OBJECTIVES In this study, we hypothesized that dietary salt intake may be related with inflammation and albuminuria independently from blood pressure (BP) in non-diabetic hypertensive patients. SUBJECTS/METHODS A total of 224 patients with primary hypertension were included in the study. Serum C-reactive protein (CRP) levels, 24-h urine sodium and albumin excretion were measured in all patients. The subjects were divided into tertiles according to the level of 24-h urinary sodium excretion: low-salt-intake group (n = 76, mean urine sodium: 111.7 ± 29.1 mmol/24 h), medium-salt-intake group (n = 77, mean urine sodium: 166.1 ± 16.3 mmol/24 h) and high-salt-intake group (n = 71, mean urine sodium: 263.6 ± 68.3 mmol/24 h). RESULTS Systolic and diastolic BP measurements of patients were similar in the three salt-intake groups. CRP and urinary albumin levels were significantly higher in high-salt-intake group compared with medium- and low-salt-intake groups (P = 0.0003 and P = 0.001, respectively). CRP was positively correlated with 24-h urinary sodium excretion (r = 0.28, P = 0.0008) and albuminuria, whereas albuminuria was positively correlated with 24-h urinary sodium excretion (r = 0.21, P = 0.0002). Multiple regression analysis revealed that urinary sodium excretion was an independent predictor of both CRP and albuminuria. CONCLUSIONS These findings suggest that high salt intake is associated with enhanced inflammation and target organ damage reflected by increased albuminuria in treated hypertensive patients independent of any BP effect.
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Antonelli A, Fallahi P, Ferrari SM, Ghiadoni L, Virdis A, Mancusi C, Centanni M, Taddei S, Ferrannini E. High serum levels of CXC (CXCL10) and CC (CCL2) chemokines in untreated essential hypertension. Int J Immunopathol Pharmacol 2012; 25:387-95. [PMID: 22697070 DOI: 10.1177/039463201202500208] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Hypertension has been suggested to exert pro-inflammatory actions through increased expression of several mediators, including chemokines. Chemokines are involved in inflammatory and autoimmune disorders, and in the formation of atherosclerotic lesions through promotion of inflammatory cell migration. The aim of this study is to evaluate the influence of high blood pressure on circulating levels of the prototype chemokines C-X-C motif ligand (CXCL)10 and C-C motif ligand (CCL)2 in 140 patients with essential hypertension not affected by thyroid disorders or overt autoimmune or inflammatory diseases, and 140 gender- and age-matched healthy controls. Mean CXCL10 and CCL2 levels were significantly higher in hypertensive patients than in controls. Among hypertensive patients, chemokines levels were higher in those with systo-diastolic hypertension compared to those with isolated systolic hypertension. In a multiple linear regression model using CXCL10 or CCL2 as dependent variables and age, body mass index, glycemia, serum creatinine, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, triglycerides, and systolic or diastolic blood pressure values as covariates, only systolic or diastolic blood pressure values were significantly related to CXCL10 or CCL2 levels. In conclusion, this study demonstrates increased circulating levels of the prototype chemokines CXCL10 and CCL2 in patients with hypertension.
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Affiliation(s)
- A Antonelli
- Department of Internal Medicine, Metabolism Unit, University of Pisa-School of Medicine, Pisa, Italy.
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Wakabayashi Y, Usui Y, Okunuki Y, Kezuka T, Takeuchi M, Iwasaki T, Ohno A, Goto H. Increases of vitreous monocyte chemotactic protein 1 and interleukin 8 levels in patients with concurrent hypertension and diabetic retinopathy. Retina 2012; 31:1951-7. [PMID: 21610567 DOI: 10.1097/iae.0b013e31820d3cee] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE To investigate whether concurrent hypertension affects vitreous cytokine levels in diabetic retinopathy. METHODS Vitreous samples from 41 patients with diabetic retinopathy with or without concurrent hypertension, who underwent vitrectomy, were collected. Vitreous cytokine concentrations were simultaneously measured using flow cytometry. Patients were stratified according to hypertension or other clinical conditions, and the differences in vitreous levels of monocyte chemotactic protein 1, interleukin 8, vascular endothelial growth factor, interferon-inducible protein 10, and monokine induced by interferon gamma were examined. RESULTS Vitreous levels of monocyte chemotactic protein 1 and interleukin 8 were significantly (P < 0.05) higher in hypertensive patients than in nonhypertensive patients and were significantly (P < 0.05) higher in active diabetic retinopathy than in inactive diabetic retinopathy. Vitreous levels of vascular endothelial growth factor, interferon-inducible protein 10, and monokine induced by interferon gamma were not affected by the coexistence of hypertension. In multivariate models, active diabetic retinopathy (P = 0.004 and P = 0.007), systolic blood pressure (P = 0.039 and P = 0.041), and hypertension (P = 0.032 and P = 0.035) were significant and independent predictors for increased vitreous monocyte chemotactic protein 1 and interleukin 8 levels. CONCLUSION Both monocyte chemotactic protein 1 and interleukin 8 levels were elevated in the vitreous of patients with diabetic retinopathy and concurrent hypertension. These findings may help to explain the epidemiologic and clinical evidence that systemic hypertension exacerbates diabetic retinopathy.
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Affiliation(s)
- Yoshihiro Wakabayashi
- Department of Ophthalmology, Hachiouji Medical Center, Tokyo Medical University, Tokyo, Japan.
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Maggio ABR, Farpour-Lambert NJ, Montecucco F, Pelli G, Marchand LM, Schwitzgebel V, Mach F, Aggoun Y, Beghetti M. Elevated E-selectin and diastolic blood pressure in diabetic children. Eur J Clin Invest 2012; 42:303-309. [PMID: 21880038 DOI: 10.1111/j.1365-2362.2011.02583.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Cardiovascular risk markers are related to micro-angiopathy in children with type 1 diabetes (T1DM), but there is no information about their relationship with blood pressure (BP) and endothelial function. MATERIALS AND METHODS This was a case-control study including 29 children with T1DM (mean age 10·5 ± 2·7 years, disease duration: 3·8 ± 2·2 years) and 39 healthy controls (mean age: 9·8 ± 2·7 years). We assessed 24-h ambulatory BP, vascular function and serum level of lipids, vascular cell adhesion molecule-1 (VCAM-1; ICAM) and selectins (E-selectin; P-selectin). RESULTS The subject groups had similar physical characteristics and lipids level, except body mass index (BMI) which was higher in T1DM than in healthy children (18·6 ± 2·6 vs. 16·7 ± 2·5 kg/m(2), P = 0·003). Children with T1DM had increased 24 h diastolic BP z-score (0·62 ± 0·9 vs. -0·65 ± 0·8, P < 0·001), even after adjustment for BMI, as well as higher VCAM-1 concentration (492 ± 346 vs. 340 ± 225 ng/mL, P = 0·039) compared to healthy subjects. Diastolic BP z-scores were associated with disease duration, E-selectin and triglyceride levels in the T1DM group (P < 0·05). E-selectin was also related to triglycerides, otherwise there were no relationships between vascular function, markers and BP. CONCLUSION E-selectin, an early atherosclerosis biomarker, is positively associated with diastolic BP values in children with T1DM, despite relatively short disease duration.
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Affiliation(s)
- Albane B R Maggio
- Paediatric Cardiology Unit, Department of Child and Adolescent, University Hospitals of Geneva, Rue Willy-Donzé, Geneva, Switzerland.
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Microalbuminuria and sRAGE in high-risk hypertensive patients treated with nifedipine/telmisartan combination treatment: a substudy of TALENT. Mediators Inflamm 2012; 2012:874149. [PMID: 22474401 PMCID: PMC3306936 DOI: 10.1155/2012/874149] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Revised: 11/15/2011] [Accepted: 11/24/2011] [Indexed: 01/17/2023] Open
Abstract
Some antihypertensive drugs have also renoprotective and anti-inflammatory properties that go beyond their effect on blood pressure. It has been suggested that microalbuminuria and glomerular filtration rate (GFR) are associated with circulating levels of the soluble form of the receptor, sRAGE (soluble receptor for advanced glycation ends-products). In the present analysis, we used data from the TALENT study to evaluate soluble receptor for advanced glycation end-products (sRAGE) plasma levels in patients with hypertension and high-cardiovascular risk-treated nifedipine and telmisartan in combination. Treatment with nifedipine-telmisartan significantly decreased mean systolic and diastolic ambulatory blood pressure and resulted in a significant increase in sRAGE plasma concentrations after 24 weeks of therapy. We concluded that in hypertensive patients with early-stage renal disease, sRAGE concentrations are not influenced by either microalbuminuria or GFR. Long-term treatment with a combination of nifedipine-telmisartan may have a beneficial effect increasing sRAGE plasma levels, thus exerting an atheroprotective and anti-inflammatory activity.
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Vascular Targets for Ischemic Stroke Treatment. Transl Stroke Res 2012. [DOI: 10.1007/978-1-4419-9530-8_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Association between human metapneumovirus seroprevalence and hypertension in elderly subjects in a long-term care facility. Hypertens Res 2011; 34:474-8. [PMID: 21248755 DOI: 10.1038/hr.2010.268] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Recently, relations between hypertension and infections caused by several pathogens have been reported. However, few studies have examined the relationship between human metapneumovirus (hMPV) and hypertension in elderly inpatients. To assess the association between anti-hMPV-immunoglobulin G (IgG) titer and the prevalence of hypertension, we conducted a case-control study in a Japanese long-term care facility (LTCF). The participants included 84 hypertensive patients aged 65 years, and 84 age- and sex-matched normotensive controls (38 males and 46 females in each group; cases, 79.9±8.4 (s.d.) years; controls, 80.1±8.3 years). Data on underling chronic clinical conditions were collected. Titers were measured using an immunofluorescence assay kit. The significance of risk factor differences was analyzed using univariate and multivariate comparisons of cases and controls. All serum samples were positive for hMPV, and IgG titers ranged from 40-fold to more than 5120-fold. There were no significant sex- or age-related differences in log(2) (anti-hMPV-IgG titer/10) among the subjects. Compared with normotensive subjects, hypertensive patients presented significantly higher log(2) (anti-hMPV-IgG titer/10) values (P<0.001). After adjustment with multiple logistic analysis, the odds ratio for log(2) (anti-hMPV-IgG titer/10) was 1.42 (95% confidence interval 1.16-1.75, P=0.001) relative to normotensive subjects. In all subjects, stepwise multiple regression analysis revealed that both hypertension and a poor nutritional state independently contributed to increased log(2) (anti-hMPV-IgG titer/10). These observations suggest that an increased anti-hMPV-IgG titer was closely related to hypertension in elderly subjects in a Japanese LTCF.
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Inflammatory activation in children with primary hypertension. Pediatr Nephrol 2010; 25:1711-8. [PMID: 20495830 DOI: 10.1007/s00467-010-1548-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2010] [Revised: 03/03/2010] [Accepted: 04/17/2010] [Indexed: 12/14/2022]
Abstract
Low-grade inflammation plays a role in the pathogenesis of primary hypertension (PH) and target organ damage (TOD). We evaluated the profile of inflammatory mediators (CRP, RANTES, MIP-1beta, MIP-1alpha, MCP-1, IL-6, angiogenin, adiponectin) in 30 healthy children (12.7 +/- 3.3 years) and 44 patients with untreated PH (13.7 +/- 2.7 years; n.s). Patients had greater concentrations of CRP, MIP-1beta, and RANTES than controls (all p < 0.05). Children with metabolic syndrome (MS) had greater CRP than children without MS (p = 0.007) and CRP correlated with number of MS criteria, body mass index (BMI), visceral fat, deep subcutaneous fat assessed by magnetic resonance imaging, carotid intima-media thickness (cIMT), left ventricular mass index, and markers of oxidative stress. RANTES correlated with cholesterol, LDL cholesterol, ApoB, and ApoB/ApoA1. Angiogenin correlated with BMI, waist circumference, visceral fat, uric acid, and patients with cIMT>2SD had greater concentration of angiogenin than those with normal cIMT (p = 0.03). Adiponectin was lower in patients with cIMT>2SD than in those with normal cIMT (p = 0.02). No model explaining variability of TOD has been built. Elevated RANTES and MIP-1beta and normal IL-6 and TNF-alpha levels indicate a vascular inflammatory process. Lack of correlation between CRP and chemokines suggests that vascular inflammation in PH precedes the systemic inflammatory changes.
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Larson AJ, Symons JD, Jalili T. Quercetin: A Treatment for Hypertension?-A Review of Efficacy and Mechanisms. Pharmaceuticals (Basel) 2010; 3:237-250. [PMID: 27713250 PMCID: PMC3991028 DOI: 10.3390/ph3010237] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Revised: 01/12/2010] [Accepted: 01/14/2010] [Indexed: 12/21/2022] Open
Abstract
Quercetin is a polyphenolic flavonoid. Common sources in the diet are apples, onions, berries, and red wine. Epidemiological studies have found an inverse relationship between dietary quercetin intake and cardiovascular disease. This has led to in vitro, in vivo, and clinical research to determine the mechanism by which quercetin exerts cardio-protective effects. Recent studies have found a reduction in blood pressure when hypertensive (>140 mm Hg systolic and >90 mm Hg diastolic) animals and humans are supplemented with quercetin. Proposed mechanisms for the antihypertensive effect of quercetin include decreased oxidative stress, inhibition of angiotensin converting enzyme activity, improved endothelial function, direct action on the vascular smooth muscle, and/or modulation in cell signaling and gene expression. Although in vitro and in vivo evidence exists to support and refute each possibility, it is likely that quercetin influences multiple targets via a combination of known and as yet undiscovered mechanisms. The purpose of this review is to examine the mechanisms whereby quercetin might reduce blood pressure in hypertensive individuals.
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Affiliation(s)
- Abigail J Larson
- Department of Exercise and Sport Science, University of Utah, HPER North, 250 South 1850 East, SLC UT, 84112, USA.
| | - J David Symons
- Department of Exercise and Sport Science, University of Utah, HPER North, 250 South 1850 East, SLC UT, 84112, USA.
| | - Thunder Jalili
- Department of Nutrition, University of Utah, HPER North, 250 South 1850 East, SLC UT 84112, USA.
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Androulakis ES, Tousoulis D, Papageorgiou N, Tsioufis C, Kallikazaros I, Stefanadis C. Essential hypertension: is there a role for inflammatory mechanisms? Cardiol Rev 2009; 17:216-221. [PMID: 19690472 DOI: 10.1097/crd.0b013e3181b18e03] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Inflammation is a key feature in the initiation, progression, and clinical implications of cardiovascular disorders, including essential hypertension. Increasing evidence shows that activation of renin-angiotensin-aldosterone system and enhanced local production of angiotensin II have been implicated in the pathophysiology of inflammation. Besides being a potent vasoactive peptide, angiotensin II regulates the inflammatory process. Specifically, it increases vascular permeability, participates in the recruitment of inflammatory cells and their adhesion to the activated endothelium, and regulates cell growth and fibrosis. Reactive oxygen species are implicated at every stage in inflammation and activate multiple intracellular signaling molecules and transcription factors associated with inflammatory responses, such as nuclear factor-kappa B and activator protein-1. Other components of the renin-angiotensin-aldosterone system, including aldosterone and/or mineralocorticoid receptor, induce the production of reactive oxygen species and participate in vascular inflammation. Several studies suggest a role of endothelin-1 as an important mediator of chronic inflammation and there is an increasing interest in the relationship between endothelin-1 and reactive oxygen species. These data may have great impact on future therapeutic strategies.
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Affiliation(s)
- Emmanuel S Androulakis
- First Cardiology Unit, Hippokration Hospital, Athens University Medical School, Athens, Greece
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Sullivan JC, Pardieck JL, Doran D, Zhang Y, She JX, Pollock JS. Greater fractalkine expression in mesenteric arteries of female spontaneously hypertensive rats compared with males. Am J Physiol Heart Circ Physiol 2009; 296:H1080-8. [PMID: 19201996 DOI: 10.1152/ajpheart.01093.2008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
A mircoarray analysis was performed to identify novel inflammatory genes that are differentially expressed in the mesenteric arteries of male and female spontaneously hypertensive rats (SHRs). Fractalkine was found to be the inflammatory gene with the greatest differential expression in mesenteric arteries, with the expression being greater in female SHRs compared with males. Greater inflammatory mediators in female SHRs were verified by measuring urinary monocyte chemoattractant protein-1, transforming growth factor-beta, and tumor necrosis factor-alpha (TNF-alpha) excretion, all of which were greater in female SHRs compared with males. Real-time PCR, Western blot analysis, and ELISA verified greater soluble fractalkine in mesenteric arteries of female SHRs. Consistent with increased fractalkine expression, TNF-alpha-converting enzyme and TNF-alpha levels in mesenteric arteries were also greater in female SHRs. We next tested the hypothesis that mesenteric arteries from female SHRs will have greater fractalkine-induced dysfunction. Acetylcholine, sodium nitroprusside, phenylephrine, and KCl concentration-response curves were performed in third-order mesenteric arteries from male and female SHRs pretreated with either vehicle or fractalkine (1 microg/ml). Fractalkine decreased sensitivity to 1) acetylcholine in arteries from male SHRs, 2) phenylephrine in arteries from both sexes, and 3) KCl in arteries from female SHRs. In conclusion, urinary and vascular markers of inflammation are greater in female SHRs compared with males, although blood pressure and cardiovascular risk are less in females.
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Affiliation(s)
- Jennifer C Sullivan
- Vascular Biology Center, Medical College of Biotechnology and Genome Medicine, Medical College of Georgia, Austa, George, USA.
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Pradhan L, Mondal D, Chandra S, Ali M, Agrawal KC. Molecular analysis of cocaine-induced endothelial dysfunction: role of endothelin-1 and nitric oxide. Cardiovasc Toxicol 2008; 8:161-71. [PMID: 18813882 DOI: 10.1007/s12012-008-9025-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2008] [Accepted: 09/10/2008] [Indexed: 12/01/2022]
Abstract
Cocaine remains the most frequently used illicit substance. Although cocaine-induced atherosclerosis is well documented, its mechanism of action on human vascular endothelial cells has not been determined. Nitric oxide (NO) and endothelin-1 (ET-1) are involved in endothelial cell activation and leukocyte recruitment. The present study monitored the effects of cocaine on NO and ET-1 production in human aortic endothelial cells (HAECs) and the effects of sodium nitroprusside (SNP) and BQ-123 on leukocyte adhesion to HAECs. Acute exposure to cocaine (1 and 3 muM) significantly increased ET-1 production (2-fold) and ET-1 receptor type-A (ET(A)R) protein expression, within 6-12 h. Cocaine exposure for a longer duration (24-72 h) showed a temporal decrease in both NO production and endothelial NO-synthase (eNOS) expression. The cocaine-mediated suppression of NO was ameliorated by co-treatment of cells with the ET(A)R blocker, BQ-123 (5 muM). Furthermore, both short-term (24 h) and long-term (72 h) exposure to cocaine increased endothelial adhesion of monocytes (U937 cells) by 20% and 40%, respectively, which were also suppressed by BQ-123 and SNP co-treatment. These data suggest that a concomitant increase in both ET-1 and ET(A)R expression in cocaine exposed HAECs may enhance signaling via the ET(A)R which decreases eNOS expression and NO production, and ultimately results in endothelial activation and leukocyte adhesion. Our findings implicate a molecular mechanism of action of cocaine and a therapeutic effect of ET(A)R-specific inhibitor in suppressing the cocaine-induced endothelial dysfunction.
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Affiliation(s)
- Leena Pradhan
- Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue SL-83, New Orleans, LA 70112, USA
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Vascular inflammation in absence of blood pressure elevation in transgenic murine model overexpressing endothelin-1 in endothelial cells. J Hypertens 2008; 26:1102-9. [DOI: 10.1097/hjh.0b013e3282fc2184] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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