|
1
|
Jurgens SM, Prieto S, Hayes JP. Inflammatory biomarkers link perceived stress with metabolic dysregulation. Brain Behav Immun Health 2023; 34:100696. [PMID: 37928770 PMCID: PMC10623170 DOI: 10.1016/j.bbih.2023.100696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 11/07/2023] Open
Abstract
Objective Perceived stress has been identified as a risk factor for metabolic syndrome. However, the intermediate pathways underlying this relationship are not well understood. Inflammatory responses may be one process by which stress leads to metabolic dysregulation. Prior work has shown that chronic stress is associated with elevated systemic inflammation and that altered inflammatory activity contributes to the pathogenesis of metabolic syndrome. The current analyses tested this hypothesis by examining inflammation as a pathway by which perceived stress affects metabolic health. Methods Data from the Midlife in the United States Study (MIDUS) (N = 648; Mean age = 52.3) provided measures of perceived stress, inflammatory biomarkers [C-reactive protein (CRP), interleukin-6 (IL-6), E-selectin, fibrinogen, intracellular adhesion molecule-1 (ICAM-1)] and metabolic health markers. Confirmatory factor analysis (CFA) was used to confirm the fit of a hierarchical model of metabolic syndrome in our sample. Structural equation modeling (SEM) was used to test the assumption that inflammation mediates the association between perceived stress and the latent factor representing metabolic syndrome. Results The CFA of metabolic syndrome demonstrated excellent goodness of fit to our sample [CFI = 0.97, TLI = 0.95, RMSEA = 0.06, SMSR = 0.05]. Mediation analysis with SEM revealed that the indirect pathway linking stress to metabolic dysregulation through inflammation was significant [B = 0.08, SE = 0.01, z = 3.69, p < .001, 95% confidence interval CI (0.04, 0.13)]. Conclusions These results suggest that inflammatory biomarkers are a viable explanatory pathway for the relationship between perceived stress and metabolic health consequences. Interventions that target psychosocial stress may serve as cost-effective and accessible treatment options for mitigating inflammatory health risks.
Collapse
Affiliation(s)
- Savana M. Jurgens
- Department of Psychology, The Ohio State University, Columbus, OH, United States
| | - Sarah Prieto
- Department of Psychology, The Ohio State University, Columbus, OH, United States
| | - Jasmeet P. Hayes
- Department of Psychology, The Ohio State University, Columbus, OH, United States
- Chronic Brain Injury Initiative, The Ohio State University, Columbus, OH, United States
| |
Collapse
|
|
2
|
Ma J, Li Y, Yang X, Liu K, Zhang X, Zuo X, Ye R, Wang Z, Shi R, Meng Q, Chen X. Signaling pathways in vascular function and hypertension: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023; 8:168. [PMID: 37080965 PMCID: PMC10119183 DOI: 10.1038/s41392-023-01430-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/03/2023] [Accepted: 03/31/2023] [Indexed: 04/22/2023] Open
Abstract
Hypertension is a global public health issue and the leading cause of premature death in humans. Despite more than a century of research, hypertension remains difficult to cure due to its complex mechanisms involving multiple interactive factors and our limited understanding of it. Hypertension is a condition that is named after its clinical features. Vascular function is a factor that affects blood pressure directly, and it is a main strategy for clinically controlling BP to regulate constriction/relaxation function of blood vessels. Vascular elasticity, caliber, and reactivity are all characteristic indicators reflecting vascular function. Blood vessels are composed of three distinct layers, out of which the endothelial cells in intima and the smooth muscle cells in media are the main performers of vascular function. The alterations in signaling pathways in these cells are the key molecular mechanisms underlying vascular dysfunction and hypertension development. In this manuscript, we will comprehensively review the signaling pathways involved in vascular function regulation and hypertension progression, including calcium pathway, NO-NOsGC-cGMP pathway, various vascular remodeling pathways and some important upstream pathways such as renin-angiotensin-aldosterone system, oxidative stress-related signaling pathway, immunity/inflammation pathway, etc. Meanwhile, we will also summarize the treatment methods of hypertension that targets vascular function regulation and discuss the possibility of these signaling pathways being applied to clinical work.
Collapse
Affiliation(s)
- Jun Ma
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Yanan Li
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xiangyu Yang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Kai Liu
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xin Zhang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xianghao Zuo
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Runyu Ye
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Ziqiong Wang
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Rufeng Shi
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China
| | - Qingtao Meng
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Xiaoping Chen
- Department of Cardiology, West China Hospital, Sichuan University, No. 37, Guo Xue District, Chengdu, Sichuan, 610041, People's Republic of China.
| |
Collapse
|
|
3
|
Bao M, Song Y, Wu S, Li J. Influence of Hypersensitive C-Reactive Protein on the Effect of Continuous Antihypertensive Pharmacological Therapy. J Cardiovasc Pharmacol 2022; 80:62-69. [PMID: 35384909 PMCID: PMC9249075 DOI: 10.1097/fjc.0000000000001267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/06/2022] [Indexed: 11/25/2022]
Abstract
ABSTRACT Systemic chronic inflammation, represented by hypersensitive C-reactive protein (hsCRP), is an essential contributing factor to hypertension. However, the influence of hsCRP levels on the effect of antihypertensive pharmacological therapy remains unknown. We evaluated hsCRP levels in 3756 newly diagnosed, untreated hypertensive subjects. Participants were grouped by tertiles of hsCRP and were randomly treated with nitrendipine + captopril, nitrendipine + spironolactone hydrochlorothiazide + captopril, and hydrochlorothiazide + spironolactone. Blood pressure (BP) was recorded every 2 weeks. A multivariate mixed linear model was used to evaluate the impact of baseline hsCRP levels on the continuous antihypertensive effect. After 3, 6, 9, and 12 months of continuous antihypertensive treatment, no significant difference was observed in BP decline among the different hsCRP groups. We identified interactions between baseline hsCRP levels and follow-up time. After adjusting for conventional risk factors and the interactions between hsCRP and follow-up time, there was no significant association between baseline hsCRP level and antihypertensive effects at 0-6 months of follow-up. However, from 6 to 12 months, subjects with higher baseline hsCRP levels exhibited a more marked BP-lowering effect ( P < 0.001 at 9 months, P = 0.002 at 12 months). Overall, there exist interaction effects between baseline hsCRP levels and follow-up time. Individuals with higher baseline hsCRP levels may exhibit a better response to antihypertensive therapy.
Collapse
Affiliation(s)
- Minghui Bao
- Department of Cardiology, Peking University First Hospital, Peking University, Beijing, China
| | - Yongjian Song
- Department of Cardiology, Zhangjiakou First Hospital, Hebei, China; and
| | - Shouling Wu
- Department of Cardiology, Kailuan Hospital, North China University of Science and Technology, Tangshan, China
| | - Jianping Li
- Department of Cardiology, Peking University First Hospital, Peking University, Beijing, China
| |
Collapse
|
|
4
|
Lin Y, Wang X, Lenz L, Ndiaye O, Qin J, Wang X, Huang H, Jeuland MA, Zhang J. Dried Blood Spot Biomarkers of Oxidative Stress and Inflammation Associated with Blood Pressure in Rural Senegalese Women with Incident Hypertension. Antioxidants (Basel) 2021; 10:antiox10122026. [PMID: 34943129 PMCID: PMC8698702 DOI: 10.3390/antiox10122026] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/16/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
Blood biomarkers of oxidative stress and inflammation have been associated with increased risk of hypertension development; yet their application in sub-Saharan Africa has been limited due to the lack of blood collection facilities. In this study, we evaluated the usefulness of dried blood spots (DBS), a more feasible alternative to venous blood, in rural sub-Saharan residents. We recruited 342 women with incident hypertension from rural Senegal, and measured C-reactive protein (CRP) and malondialdehyde (MDA) in DBS and concurrent blood pressure (BP) at baseline and 1-year follow-up. Associations of DBS biomarkers with current levels of and 1-year changes in BP were examined after adjusting for demographic, medical, and socioeconomic covariates. DBS concentrations of MDA were significantly associated with concurrent systolic BP (SBP) (p < 0.05), while DBS baseline concentrations of CRP were associated with longitudinal changes in SBP between baseline and follow-up. Compared to participants with baseline CRP < 1 mg/L, those with CRP of 1–3 mg/L and 3–10 mg/L had 2.11 mmHg (95%CI: −2.79 to 7.02 mmHg) and 4.68 mmHg (95%CI: 0.01 to 9.36 mmHg) increases in SBP at follow-up, respectively. The results support the use of DBS biomarkers for hypertension prevention and control, especially in settings with limited clinical resources.
Collapse
Affiliation(s)
- Yan Lin
- Nicholas School of the Environment & Duke Global Health Institute, Duke University, Durham, NC 27705, USA; (Y.L.); (X.W.); (J.Q.); (X.W.); (H.H.)
| | - Xiangtian Wang
- Nicholas School of the Environment & Duke Global Health Institute, Duke University, Durham, NC 27705, USA; (Y.L.); (X.W.); (J.Q.); (X.W.); (H.H.)
| | - Luciane Lenz
- RWI Leibniz Institute for Economic Research, 10115 Berlin, Germany; (L.L.); (M.A.J.)
| | - Ousmane Ndiaye
- Centre de Recherche pour le Développement Economique et Social (CRDES), Université Gaston-Berger, Saint-Louis, P.O. Box 234, Senegal;
| | - Jian Qin
- Nicholas School of the Environment & Duke Global Health Institute, Duke University, Durham, NC 27705, USA; (Y.L.); (X.W.); (J.Q.); (X.W.); (H.H.)
- School of Public Health, Guangxi Medical University, Nanning 530021, China
| | - Xiaoli Wang
- Nicholas School of the Environment & Duke Global Health Institute, Duke University, Durham, NC 27705, USA; (Y.L.); (X.W.); (J.Q.); (X.W.); (H.H.)
- School of Environmental Science and Safety Engineering, Tianjin University of Technology, Tianjin 300387, China
| | - Hui Huang
- Nicholas School of the Environment & Duke Global Health Institute, Duke University, Durham, NC 27705, USA; (Y.L.); (X.W.); (J.Q.); (X.W.); (H.H.)
- College of Public Health, Zhengzhou University, Zhengzhou 450001, China
| | - Marc A. Jeuland
- RWI Leibniz Institute for Economic Research, 10115 Berlin, Germany; (L.L.); (M.A.J.)
- Sanford School of Public Policy and Duke Global Health Institute, Duke University, Durham, NC 27705, USA
| | - Junfeng Zhang
- Nicholas School of the Environment & Duke Global Health Institute, Duke University, Durham, NC 27705, USA; (Y.L.); (X.W.); (J.Q.); (X.W.); (H.H.)
- Correspondence:
| |
Collapse
|
|
5
|
Wu SJ, Shi ZW, Wang X, Ren FF, Xie ZY, Lei L, Chen P. Activation of the Cholinergic Anti-inflammatory Pathway Attenuated Angiotension II-Dependent Hypertension and Renal Injury. Front Pharmacol 2021; 12:593682. [PMID: 33815099 PMCID: PMC8010129 DOI: 10.3389/fphar.2021.593682] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Angiotensin II (AngII) induces renal fibrosis, characterized by fibroblast proliferation, inflammatory cell infiltration and excessive extracellular matrix deposition, all of which was relevant closely to hypertension. The vagus nerve-related cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses. The aim of present study was to determine the effect of CAP on renal inflammation and fibrosis. Methods and Results: AngII-induced hypertension was induced in vivo by 14-days low-dose AngII infusion from osmotic minipumps. We used GTS-21 dihydrochloride, a selective nicotinic acetylcholine receptor agonist. Daily intraperitoneal GTS-21 injection and/or vagotomy started after hypertension was confirmed and continued for 4 weeks. The elevated blood pressure caused by AngII was significantly attenuated by GTS-21. Improved baroreflex sensitivity was observed after GTS-21 administration. Masson stain and immunoblotting revealed that deposition of excessive fibrosis and overexpression of inflammatory cytokines induced by AngII was reduced by GTS-21. To determine the role of autonomic control in CAP, unilateral vagotomy was performed. Vagotomy weakened the effect of CAP on AngII-induced hypertension. In vitro, GTS-21 suppressed NF-κB activation, attenuated AngII-induced epithelial-mesenchymal transition and reduced inflammation and fibrosis in NRK-52E cells; α-bungarotoxin (α-Bgt, an α7-nAChR selective antagonist) partly inhibited these effects. Conclusion: CAP protected against AngII-induced hypertension via improvement in autonomic control, suppression of NF-κB activation, and reduction of renal fibrosis and inflammatory response.
Collapse
Affiliation(s)
- Shu-Jie Wu
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhe-Wei Shi
- Department of Cardiology, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, China
| | - Xue Wang
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fang-Fang Ren
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zuo-Yi Xie
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li Lei
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Peng Chen
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
6
|
Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by inhibiting the AMPK-eNOS axis. Clin Sci (Lond) 2021; 134:1805-1819. [PMID: 32639009 DOI: 10.1042/cs20200137] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/05/2020] [Accepted: 07/08/2020] [Indexed: 12/13/2022]
Abstract
Successful treatment of resistant hypertension accompanied by elevated human C-reactive protein (hCRP) remains a key challenge in reducing the burden of cardiovascular diseases. It is still unclear whether clinically relevant high-level hCRP is merely a marker or a key driver of hypertension. Here, we investigated the role and mechanism of clinically relevant high level of hCRP in hypertension. Elevated blood pressure was observed in all three hCRP overexpression models, including adeno-associated virus 9 (AAV9)-transfected mice, AAV9-transfected rats and hCRP transgenic (hCRPtg) rats. hCRPtg rats expressing clinically relevant high-level hCRP developed spontaneous hypertension, cardiac hypertrophy, myocardial fibrosis and impaired endothelium-dependent relaxation. Mechanistically, studies in endothelial nitric oxide (NO) synthase (eNOS) knockout mice transfected with AAV9-hCRP and phosphoproteomics analysis of hCRP-treated endothelial cells revealed that hCRP inhibited AMP-activated protein kinase (AMPK)-eNOS phosphorylation pathway. Further, activation of AMPK by metformin normalized endothelial-dependent vasodilation and decreased the blood pressure of hCRPtg rats. Our results show that clinically relevant high-level hCRP induces hypertension and endothelial dysfunction by inhibiting AMPK-eNOS signaling, and highlight hCRP is not only an inflammatory biomarker but also a driver of hypertension. Treatment with metformin or a synthetic AMPK activator may be a potential strategy for vaso-dysfunction and hypertension in patients with high hCRP levels.
Collapse
|
|
7
|
Rothman AM, MacFadyen J, Thuren T, Webb A, Harrison DG, Guzik TJ, Libby P, Glynn RJ, Ridker PM. Effects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk: A Secondary Analysis of CANTOS. Hypertension 2019; 75:477-482. [PMID: 31884854 PMCID: PMC7055941 DOI: 10.1161/hypertensionaha.119.13642] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Supplemental Digital Content is available in the text. While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1β inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo. A total of 9549 trial participants had blood pressure recordings during follow-up; of these, 80% had a preexisting diagnosis of hypertension. In patients without baseline hypertension, rates of incident hypertension were 23.4, 26.6, and 28.1 per 100-person years for the lowest to highest baseline tertiles of hsCRP (P>0.2). In all participants random allocation to canakinumab did not reduce blood pressure (P>0.2) or incident hypertension during the follow-up period (hazard ratio, 0.96 [0.85–1.08], P>0.2). IL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates. These analyses suggest that the mechanisms underlying this benefit are not related to changes in blood pressure or incident hypertension.
Collapse
Affiliation(s)
- Alexander Mk Rothman
- From the Department of Cardiology, Chesterman Cardiothoracic Unit, Northern General Hospital, Sheffield, United Kingdom (A.M.K.R.).,Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, United Kingdom (A.M.K.R.)
| | - Jean MacFadyen
- Center for Cardiovascular Disease Prevention (J.M., R.J.G., P.M.R.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Tom Thuren
- Novartis Pharmaceutical Corporation, One Health Plaza, East Hanover, NJ (T.T.)
| | - Alastair Webb
- Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences, University of Oxford, United Kingdom (A.W.)
| | | | - Tomasz J Guzik
- Institute of Cardiovascular and Medical Research, Queen Elizabeth University Hospital, University of Glasgow (T.J.G.).,Department of Medicine, Jagiellonian University, School of Medicine, Cracow, Poland (T.J.G.)
| | - Peter Libby
- Cardiovascular Division (P.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Robert J Glynn
- Center for Cardiovascular Disease Prevention (J.M., R.J.G., P.M.R.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Paul M Ridker
- Center for Cardiovascular Disease Prevention (J.M., R.J.G., P.M.R.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| |
Collapse
|
|
8
|
Peng J, Vongpatanasin W, Sacharidou A, Kifer D, Yuhanna IS, Banerjee S, Tanigaki K, Polasek O, Chu H, Sundgren NC, Rohatgi A, Chambliss KL, Lauc G, Mineo C, Shaul PW. Supplementation With the Sialic Acid Precursor N-Acetyl-D-Mannosamine Breaks the Link Between Obesity and Hypertension. Circulation 2019; 140:2005-2018. [PMID: 31597453 PMCID: PMC7027951 DOI: 10.1161/circulationaha.119.043490] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension. METHODS Involvement of IgG was studied using IgG μ heavy chain-null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell-specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). RESULTS Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow-fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension. CONCLUSIONS Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.
Collapse
Affiliation(s)
- Jun Peng
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Wanpen Vongpatanasin
- Division of Cardiology, Dept. of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Anastasia Sacharidou
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Domagoj Kifer
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Ivan S. Yuhanna
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Subhashis Banerjee
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Keiji Tanigaki
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Ozren Polasek
- Department of Public Health, University of Split School of Medicine, Split, Croatia
| | - Haiyan Chu
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Nathan C. Sundgren
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Anand Rohatgi
- Division of Cardiology, Dept. of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Ken L. Chambliss
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Gordan Lauc
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
- Genos Glycoscience Research Laboratory, Zagreb, Croatia
| | - Chieko Mineo
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| | - Philip W. Shaul
- Center for Pulmonary and Vascular Biology, Dept. of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA 75390
| |
Collapse
|
|
9
|
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.
Collapse
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
| |
Collapse
|
|
10
|
Handley RT, Bentley RE, Brown TL, Annan AA. Successful treatment of obesity and insulin resistance via ketogenic diet status post Roux-en-Y. BMJ Case Rep 2018; 2018:bcr-2018-225643. [PMID: 30121567 PMCID: PMC6101305 DOI: 10.1136/bcr-2018-225643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/28/2018] [Indexed: 12/18/2022] Open
Abstract
This is a single case of a 65-year-old American woman who presented with substantial weight gain and insulin resistance (IR) post-Roux-en-Y gastric bypass (RYGB) surgery. Before RYGB, she had reached 340 lbs (155 kg) and a body mass index (BMI) of 56.6 kg/m2 The surgery resulted in a 70 lbs (32 kg) weight loss, bringing her BMI, per cent total weight loss (%TWL) and per cent excess weight loss (%EWL) to 44.9 kg/m2, 20.6% and 36.8%, respectively. Unfortunately, her BMI would return to 53.6 kg/m2, nearly her pre-RYGB BMI. It was then she sought the guidance of a primary care physician with expertise in nutrition and medical management of obesity, who placed her on a ketogenic diet. One year later, she had lost 102 lbs (46.4 kg), resulting in a BMI, %TWL and %EWL of 36.6 kg/m2, 31.7%, and 63.1%, respectively, also further resulting in significant improvements of her inflammatory biomarkers. This case presentation will explore current literature, covering the effects of obesity on IR, pre-diabetes and other disease-provoking inflammatory biomarkers.
Collapse
Affiliation(s)
- Richard Todd Handley
- Chief Operating Officer, Wells World Services, Valencia, California, USA
- College of Medicine, University of Science, Arts and Technology, Montserrat, BWI
| | - Ryan E Bentley
- Department of Family and Community Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, Michigan, USA
| | - Tony L Brown
- National Institutes of Health, National Cancer Institute, Bethesda, Maryland, USA
| | - Abigail A Annan
- Department of Family and Community Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, Michigan, USA
| |
Collapse
|
|
11
|
Mazidi M, Toth PP, Banach M. C-reactive Protein Is Associated With Prevalence of the Metabolic Syndrome, Hypertension, and Diabetes Mellitus in US Adults. Angiology 2017; 69:438-442. [PMID: 28914081 DOI: 10.1177/0003319717729288] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The prevalence of metabolic syndrome (MetS) has increased globally and is associated with an increased risk of cardiovascular diseases that may be related to its association with inflammation. We have assessed whether the prevalence of the MetS correlates with a serum high-sensitivity C-reactive protein (hsCRP) concentration in a population-based sample of US men and women. Participants were selected from the US National Health and Nutrition Examination Survey from 2005 to 2010. Of the 17 689 participants analyzed, 8607 (48.3%) were men. The mean age was 45.8 years in the overall sample (between men and women P = .047). The prevalence of MetS, diabetes mellitus, and hypertension increased across quartiles for hsCRP (all P < .001). Moreover, we found that for the age-, race-, sex-, and smoking-adjusted logistic regression, with increasing hsCRP, the risk of having MetS increased with an odds ratio of 5.20 (95% confidence interval, 4.54-5.93, P < .001) when comparing the highest quartile of serum hsCRP with the lowest. This study provides further evidence for an association between MetS and subclinical inflammation.
Collapse
Affiliation(s)
- Mohsen Mazidi
- 1 Key State Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.,2 Institute of Genetics and Developmental Biology, International College, University of Chinese Academy of Science, Beijing, China
| | - Peter P Toth
- 3 Department of Preventive Cardiology, CGH Medical Center, Sterling, IL, USA.,4 Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maciej Banach
- 5 Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland.,6 Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| |
Collapse
|
|
12
|
Bian A, Shi M, Flores B, Gillings N, Li P, Yan SX, Levine B, Xing C, Hu MC. Downregulation of autophagy is associated with severe ischemia-reperfusion-induced acute kidney injury in overexpressing C-reactive protein mice. PLoS One 2017; 12:e0181848. [PMID: 28886014 PMCID: PMC5590740 DOI: 10.1371/journal.pone.0181848] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 07/07/2017] [Indexed: 12/16/2022] Open
Abstract
C-reactive protein (CRP), was recently reported to be closely associated with poor renal function in patients with acute kidney injury (AKI), but whether CRP is pathogenic or a mere biomarker in AKI remains largely unclear. Impaired autophagy is known to exacerbate renal ischemia-reperfusion injury (IRI). We examined whether the pathogenic role of CRP in AKI is associated with reduction of autophagy. We mated transgenic rabbit CRP over-expressing mice (Tg-CRP) with two autophagy reporter mouse lines, Tg-GFP-LC3 mice (LC3) and Tg-RFP-GFP-LC3 mice (RG-LC3) respectively to generate Tg-CRP-GFP-LC3 mice (PLC3) and Tg-CRP-RFP-GFP-LC3 mice (PRG-LC3). AKI was induced by IRI. Compared with LC3 mice, PLC3 mice developed more severe kidney damage after IRI. Renal tubules were isolated from LC3 mice at baseline for primary culture. OKP cells were transiently transfected with GFP-LC3 plasmid. CRP addition exacerbated lactate dehydrogenase release from both cell types. Immunoblots showed lower LC-3 II/I ratios and higher levels of p62, markers of reduced autophagy flux, in the kidneys of PLC3 mice compared to LC3 mice after IRI, and in primary cultured renal tubules and OKP cells treated with CRP and H2O2 compared to H2O2 alone. Immunohistochemistry showed much fewer LC-3 punctae, and electron microscopy showed fewer autophagosomes in kidneys of PLC3 mice compared to LC3 mice after IRI. Similarly, CRP addition reduced GFP-LC3 punctae induced by H2O2 in primary cultured proximal tubules and in GFP-LC3 plasmid transfected OKP cells. Rapamycin, an autophagy inducer, rescued impaired autophagy and reduced renal injury in vivo. In summary, it was suggested that CRP be more than mere biomarker in AKI, and render the kidney more susceptible to ischemic/oxidative injury, which is associated with down-regulating autophagy flux.
Collapse
Affiliation(s)
- Ao Bian
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Mingjun Shi
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Brianna Flores
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Nancy Gillings
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Peng Li
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shirley Xiao Yan
- Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Beth Levine
- Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
- Departments of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
- Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
| | - Changying Xing
- Department of Nephrology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- * E-mail: (CX); (MCH)
| | - Ming Chang Hu
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
- Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
- * E-mail: (CX); (MCH)
| |
Collapse
|
|
13
|
Nosalski R, McGinnigle E, Siedlinski M, Guzik TJ. Novel Immune Mechanisms in Hypertension and Cardiovascular Risk. CURRENT CARDIOVASCULAR RISK REPORTS 2017; 11:12. [PMID: 28360962 PMCID: PMC5339316 DOI: 10.1007/s12170-017-0537-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Hypertension is a common disorder with substantial impact on public health due to highly elevated cardiovascular risk. The mechanisms still remain unclear and treatments are not sufficient to reduce risk in majority of patients. Inflammatory mechanisms may provide an important mechanism linking hypertension and cardiovascular risk. We aim to review newly identified immune and inflammatory mechanisms of hypertension with focus on their potential therapeutic impact. RECENT FINDINGS In addition to the established role of the vasculature, kidneys and central nervous system in pathogenesis of hypertension, low-grade inflammation contributes to this disorder as indicated by experimental models and GWAS studies pointing to SH2B3 immune gene as top key driver of hypertension. Immune responses in hypertension are greatly driven by neoantigens generated by oxidative stress and modulated by chemokines such as RANTES, IP-10 and microRNAs including miR-21 and miR-155 with other molecules under investigation. Cells of both innate and adoptive immune system infiltrate vasculature and kidneys, affecting their function by releasing pro-inflammatory mediators and reactive oxygen species. SUMMARY Immune and inflammatory mechanisms of hypertension provide a link between high blood pressure and increased cardiovascular risk, and reduction of blood pressure without attention to these underlying mechanisms is not sufficient to reduce risk.
Collapse
Affiliation(s)
- Ryszard Nosalski
- BHF Centre for Excellence Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland UK
- Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Eilidh McGinnigle
- BHF Centre for Excellence Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland UK
| | - Mateusz Siedlinski
- Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Tomasz J. Guzik
- BHF Centre for Excellence Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland UK
- Department of Internal and Agricultural Medicine, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| |
Collapse
|
|
14
|
Peri-Okonny PA, Ayers C, Maalouf N, Das SR, de Lemos JA, Berry JD, Turer AT, Neeland IJ, Scherer PE, Vongpatanasin W. Adiponectin protects against incident hypertension independent of body fat distribution: observations from the Dallas Heart Study. Diabetes Metab Res Rev 2017; 33:10.1002/dmrr.2840. [PMID: 27455039 PMCID: PMC5477232 DOI: 10.1002/dmrr.2840] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 07/07/2016] [Accepted: 07/14/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Excess adipose tissue has been implicated in the pathogenesis of insulin resistance and atherosclerosis and is a key risk factor for blood pressure (BP) elevation. However, circulating levels of adiponectin, a protein produced by adipose tissue and widely implicated in the pathogenesis of insulin resistance and atherosclerosis, are inversely proportional to adiposity. The relationship between adiponectin and incident hypertension has not been determined in the general US population. METHODS Normotensive participants (n = 1233) enrolled in the Dallas Heart Study, a multiethnic, probability-based population sample of Dallas County adults were followed for median of 7 years. Retroperitoneal, intraperitoneal, visceral, and subcutaneous adipose tissue were measured at baseline by magnetic resonance imaging. Liver fat content was measured by 1 H-magnetic resonance spectroscopy. Relative risk regression was used to determine the association of adiponectin with incident hypertension after adjustment for age, race, sex, BMI, smoking, diabetes, baseline systolic BP, total cholesterol, and regional fat depot. RESULTS Of the 1233 study participants (median age 40 years, 40% black, and 56% women), 391 (32%) had developed hypertension over a median follow-up of 7 years. Adiponectin levels were associated with reduced risk of incident hypertension (RR 0.81, 95% CI [0.68-0.96]) in the fully adjusted model, which included liver fat. Similar results were observed after adjustment for subcutaneous or visceral fat depots when tested individually or simultaneously in the model. CONCLUSION Our study suggested a protective role of adiponectin against incident hypertension independent of body fat distribution.
Collapse
Affiliation(s)
| | - Colby Ayers
- Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX
| | - Naim Maalouf
- Endocrinology Division, University of Texas Southwestern Medical Center, Dallas, TX
| | - Sandeep R. Das
- Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX
| | - James A. de Lemos
- Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX
| | - Jarett D. Berry
- Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX
- Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX
| | - Aslan T. Turer
- Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX
| | - Ian J. Neeland
- Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX
| | - Philipp E. Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX
| | - Wanpen Vongpatanasin
- Hypertension Section, University of Texas Southwestern Medical Center, Dallas, TX
- Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX
| |
Collapse
|
|
15
|
Tanigaki K, Chambliss KL, Yuhanna IS, Sacharidou A, Ahmed M, Atochin DN, Huang PL, Shaul PW, Mineo C. Endothelial Fcγ Receptor IIB Activation Blunts Insulin Delivery to Skeletal Muscle to Cause Insulin Resistance in Mice. Diabetes 2016; 65:1996-2005. [PMID: 27207525 PMCID: PMC4915578 DOI: 10.2337/db15-1605] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 04/09/2016] [Indexed: 12/12/2022]
Abstract
Modest elevations in C-reactive protein (CRP) are associated with type 2 diabetes. We previously revealed in mice that increased CRP causes insulin resistance and mice globally deficient in the CRP receptor Fcγ receptor IIB (FcγRIIB) were protected from the disorder. FcγRIIB is expressed in numerous cell types including endothelium and B lymphocytes. Here we investigated how endothelial FcγRIIB influences glucose homeostasis, using mice with elevated CRP expressing or lacking endothelial FcγRIIB. Whereas increased CRP caused insulin resistance in mice expressing endothelial FcγRIIB, mice deficient in the endothelial receptor were protected. The insulin resistance with endothelial FcγRIIB activation was due to impaired skeletal muscle glucose uptake caused by attenuated insulin delivery, and it was associated with blunted endothelial nitric oxide synthase (eNOS) activation in skeletal muscle. In culture, CRP suppressed endothelial cell insulin transcytosis via FcγRIIB activation and eNOS antagonism. Furthermore, in knock-in mice harboring constitutively active eNOS, elevated CRP did not invoke insulin resistance. Collectively these findings reveal that by inhibiting eNOS, endothelial FcγRIIB activation by CRP blunts insulin delivery to skeletal muscle to cause insulin resistance. Thus, a series of mechanisms in endothelium that impairs insulin movement has been identified that may contribute to type 2 diabetes pathogenesis.
Collapse
Affiliation(s)
- Keiji Tanigaki
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | - Ken L Chambliss
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | - Ivan S Yuhanna
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | - Anastasia Sacharidou
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | - Mohamed Ahmed
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | - Dmitriy N Atochin
- Cardiovascular Research Center and Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Paul L Huang
- Cardiovascular Research Center and Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Philip W Shaul
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | - Chieko Mineo
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| |
Collapse
|
|
16
|
Prins BP, Abbasi A, Wong A, Vaez A, Nolte I, Franceschini N, Stuart PE, Guterriez Achury J, Mistry V, Bradfield JP, Valdes AM, Bras J, Shatunov A, Lu C, Han B, Raychaudhuri S, Bevan S, Mayes MD, Tsoi LC, Evangelou E, Nair RP, Grant SFA, Polychronakos C, Radstake TRD, van Heel DA, Dunstan ML, Wood NW, Al-Chalabi A, Dehghan A, Hakonarson H, Markus HS, Elder JT, Knight J, Arking DE, Spector TD, Koeleman BPC, van Duijn CM, Martin J, Morris AP, Weersma RK, Wijmenga C, Munroe PB, Perry JRB, Pouget JG, Jamshidi Y, Snieder H, Alizadeh BZ. Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study. PLoS Med 2016; 13:e1001976. [PMID: 27327646 PMCID: PMC4915710 DOI: 10.1371/journal.pmed.1001976] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 02/03/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.
Collapse
Affiliation(s)
- Bram. P. Prins
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom
- * E-mail: (BPP); (BZA)
| | - Ali Abbasi
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom
- Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Anson Wong
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ahmad Vaez
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ilja Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Nora Franceschini
- Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
| | - Philip E. Stuart
- Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Javier Guterriez Achury
- Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Vanisha Mistry
- Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Jonathan P. Bradfield
- Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, United States of America
| | - Ana M. Valdes
- Department of Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom
| | - Jose Bras
- Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom
| | - Aleksey Shatunov
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - PAGE Consortium
- Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America
| | | | - Systemic Sclerosis consortium
- Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
- Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain
| | - Treat OA consortium
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
| | - DIAGRAM Consortium
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | | | - ALS consortium
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | | | | | - CKDGen consortium
- NHLBI’s Framingham Heart Study, Center for Population Studies and Harvard Medical School, Framingham, Massachusetts, United States of America
| | - GERAD1 Consortium
- Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | | | | | | | - Chen Lu
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
| | - Buhm Han
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
| | - Soumya Raychaudhuri
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Division of Rheumatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, United States of America
- Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
| | - Steve Bevan
- Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - Maureen D. Mayes
- Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
| | - Lam C. Tsoi
- Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Evangelos Evangelou
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Rajan P. Nair
- Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Struan F. A. Grant
- Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, United States of America
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Constantin Polychronakos
- Endocrine Genetics Research Institute, McGill University Health Center, Montreal, Quebec, Canada
| | - Timothy R. D. Radstake
- Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - David A. van Heel
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Melanie L. Dunstan
- Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Nicholas W. Wood
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
| | - Ammar Al-Chalabi
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- Complex Disease Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America
| | - Abbas Dehghan
- Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Hakon Hakonarson
- Center for Applied Genomics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, United States of America
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Hugh S. Markus
- Neurology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
| | - James T. Elder
- Department of Dermatology, Veterans Affairs Hospital, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Jo Knight
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
- Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Dan E. Arking
- McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Timothy D. Spector
- Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
| | - Bobby P. C. Koeleman
- Complex Genetic Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Cornelia M. van Duijn
- Department of Epidemiology, Erasmus University Rotterdam, University Medical Centre Rotterdam, Rotterdam, the Netherlands
| | - Javier Martin
- Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain
| | - Andrew P. Morris
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
- Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom
| | - Rinse K. Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Patricia B. Munroe
- NIHR Barts Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
- Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - John R. B. Perry
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom
| | - Jennie G. Pouget
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Yalda Jamshidi
- Cardiogenetics Lab, Cardiovascular and Cell Sciences Institute, St George’s Hospital Medical School, London, United Kingdom
| | - Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Behrooz Z. Alizadeh
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- * E-mail: (BPP); (BZA)
| |
Collapse
|
|
17
|
Michel MC, Brunner HR, Foster C, Huo Y. Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease. Pharmacol Ther 2016; 164:1-81. [PMID: 27130806 DOI: 10.1016/j.pharmthera.2016.03.019] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 02/07/2023]
Abstract
We have reviewed the effects of angiotensin II type 1 receptor antagonists (ARBs) in various animal models of hypertension, atherosclerosis, cardiac function, hypertrophy and fibrosis, glucose and lipid metabolism, and renal function and morphology. Those of azilsartan and telmisartan have been included comprehensively whereas those of other ARBs have been included systematically but without intention of completeness. ARBs as a class lower blood pressure in established hypertension and prevent hypertension development in all applicable animal models except those with a markedly suppressed renin-angiotensin system; blood pressure lowering even persists for a considerable time after discontinuation of treatment. This translates into a reduced mortality, particularly in models exhibiting marked hypertension. The retrieved data on vascular, cardiac and renal function and morphology as well as on glucose and lipid metabolism are discussed to address three main questions: 1. Can ARB effects on blood vessels, heart, kidney and metabolic function be explained by blood pressure lowering alone or are they additionally directly related to blockade of the renin-angiotensin system? 2. Are they shared by other inhibitors of the renin-angiotensin system, e.g. angiotensin converting enzyme inhibitors? 3. Are some effects specific for one or more compounds within the ARB class? Taken together these data profile ARBs as a drug class with unique properties that have beneficial effects far beyond those on blood pressure reduction and, in some cases distinct from those of angiotensin converting enzyme inhibitors. The clinical relevance of angiotensin receptor-independent effects of some ARBs remains to be determined.
Collapse
Affiliation(s)
- Martin C Michel
- Dept. Pharmacology, Johannes Gutenberg University, Mainz, Germany; Dept. Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim, Ingelheim, Germany.
| | | | - Carolyn Foster
- Retiree from Dept. of Research Networking, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
| | - Yong Huo
- Dept. Cardiology & Heart Center, Peking University First Hospital, Beijing, PR China
| |
Collapse
|
|
18
|
Canavero I, Sherburne HA, Tremble SM, Clark WM, Cipolla MJ. Effects of Acute Stroke Serum on Non-Ischemic Cerebral and Mesenteric Vascular Function. Transl Stroke Res 2016; 7:156-65. [PMID: 26809954 DOI: 10.1007/s12975-016-0449-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 12/17/2015] [Accepted: 01/08/2016] [Indexed: 02/03/2023]
Abstract
We investigated the effects of circulating factors in serum obtained from patients in the acute phase of different subtypes of ischemic stroke on non-ischemic cerebral and mesenteric arteries, as a potential mechanism involved in influencing regional perfusion and thus clinical evolution. Posterior cerebral arteries (PCAs) and mesentery arteries (MAs) isolated from Wistar Kyoto rats were perfused with serum from acute stroke patients with large vessel disease without (LVD) or with hypertension (LVD + HTN), cardioembolism with hypertension (CE + HTN), or physiologic saline as controls. Myogenic activity and nitric oxide-dependent vasorelaxation were assessed after 2 h of intraluminal exposure to serum. Vascular function was differentially affected by sera. Exposure to LVD serum increased myogenic tone and produced endothelial dysfunction in both PCAs and MAs. However, CE + HTN serum increased tone and decreased smooth muscle sensitivity to NO in vessels from both vascular beds. LVD + HTN serum was associated with reduced smooth muscle sensitivity to NO in vessels from both vascular beds but increased tone only in PCAs. Inflammation and oxidative stress, determined by measurement of high sensitivity C-reactive protein, uric acid, and free 8-isoprostane, were enhanced in all the serum groups. These results demonstrate vasoactive properties of acute stroke serum related to stroke subtypes that could potentially contribute to the pathogenesis of early hemodynamic-based clinical events.
Collapse
Affiliation(s)
- Isabella Canavero
- Department of Neurological Sciences, University of Vermont College of Medicine, 149 Beaumont Ave., HSRF 416A, Burlington, VT, 05405, USA
| | - Helene A Sherburne
- Department of Neurological Sciences, University of Vermont College of Medicine, 149 Beaumont Ave., HSRF 416A, Burlington, VT, 05405, USA
| | - Sarah M Tremble
- Department of Neurological Sciences, University of Vermont College of Medicine, 149 Beaumont Ave., HSRF 416A, Burlington, VT, 05405, USA
| | - Wayne M Clark
- Department of Neurology, Oregon Stroke Center, Oregon Health and Science University, Portland, OR, USA
| | - Marilyn J Cipolla
- Department of Neurological Sciences, University of Vermont College of Medicine, 149 Beaumont Ave., HSRF 416A, Burlington, VT, 05405, USA. .,Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Vermont College of Medicine, Burlington, VT, USA. .,Department of Pharmacology, University of Vermont College of Medicine, Burlington, VT, USA.
| |
Collapse
|
|
19
|
Tanigaki K, Sundgren N, Khera A, Vongpatanasin W, Mineo C, Shaul PW. Fcγ receptors and ligands and cardiovascular disease. Circ Res 2015; 116:368-84. [PMID: 25593280 DOI: 10.1161/circresaha.116.302795] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Fcγ receptors (FcγRs) classically modulate intracellular signaling on binding of the Fc region of IgG in immune response cells. How FcγR and their ligands affect cardiovascular health and disease has been interrogated recently in both preclinical and clinical studies. The stimulation of activating FcγR in endothelial cells, vascular smooth muscle cells, and monocytes/macrophages causes a variety of cellular responses that may contribute to vascular disease pathogenesis. Stimulation of the lone inhibitory FγcR, FcγRIIB, also has adverse consequences in endothelial cells, antagonizing NO production and reparative mechanisms. In preclinical disease models, activating FcγRs promote atherosclerosis, whereas FcγRIIB is protective, and activating FcγRs also enhance thrombotic and nonthrombotic vascular occlusion. The FcγR ligand C-reactive protein (CRP) has undergone intense study. Although in rodents CRP does not affect atherosclerosis, it causes hypertension and insulin resistance and worsens myocardial infarction. Massive data have accumulated indicating an association between increases in circulating CRP and coronary heart disease in humans. However, Mendelian randomization studies reveal that CRP is not likely a disease mediator. CRP genetics and hypertension warrant further investigation. To date, studies of genetic variants of activating FcγRs are insufficient to implicate the receptors in coronary heart disease pathogenesis in humans. However, a link between FcγRIIB and human hypertension may be emerging. Further knowledge of the vascular biology of FcγR and their ligands will potentially enhance our understanding of cardiovascular disorders, particularly in patients whose greater predisposition for disease is not explained by traditional risk factors, such as individuals with autoimmune disorders.
Collapse
Affiliation(s)
- Keiji Tanigaki
- From the Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., N.S., C.M., P.W.S.), and Division of Cardiology, Department of Internal Medicine (A.K., W.V.), University of Texas Southwestern Medical Center, Dallas
| | - Nathan Sundgren
- From the Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., N.S., C.M., P.W.S.), and Division of Cardiology, Department of Internal Medicine (A.K., W.V.), University of Texas Southwestern Medical Center, Dallas
| | - Amit Khera
- From the Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., N.S., C.M., P.W.S.), and Division of Cardiology, Department of Internal Medicine (A.K., W.V.), University of Texas Southwestern Medical Center, Dallas
| | - Wanpen Vongpatanasin
- From the Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., N.S., C.M., P.W.S.), and Division of Cardiology, Department of Internal Medicine (A.K., W.V.), University of Texas Southwestern Medical Center, Dallas
| | - Chieko Mineo
- From the Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., N.S., C.M., P.W.S.), and Division of Cardiology, Department of Internal Medicine (A.K., W.V.), University of Texas Southwestern Medical Center, Dallas
| | - Philip W Shaul
- From the Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., N.S., C.M., P.W.S.), and Division of Cardiology, Department of Internal Medicine (A.K., W.V.), University of Texas Southwestern Medical Center, Dallas.
| |
Collapse
|
|
20
|
Affiliation(s)
- Philip W Shaul
- Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas
| |
Collapse
|
|
21
|
Sundgren NC, Vongpatanasin W, Boggan BMD, Tanigaki K, Yuhanna IS, Chambliss KL, Mineo C, Shaul PW. IgG receptor FcγRIIB plays a key role in obesity-induced hypertension. Hypertension 2014; 65:456-62. [PMID: 25368023 DOI: 10.1161/hypertensionaha.114.04670] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
There is a well-recognized association between obesity, inflammation, and hypertension. Why obesity causes hypertension is poorly understood. We previously demonstrated using a C-reactive protein (CRP) transgenic mouse that CRP induces hypertension that is related to NO deficiency. Our prior work in cultured endothelial cells identified the Fcγ receptor IIB (FcγRIIB) as the receptor for CRP whereby it antagonizes endothelial NO synthase. Recognizing known associations between CRP and obesity and hypertension in humans, in the present study we tested the hypothesis that FcγRIIB plays a role in obesity-induced hypertension in mice. Using radiotelemetry, we first demonstrated that the hypertension observed in transgenic mouse-CRP is mediated by the receptor, indicating that FcγRIIB is capable of modifying blood pressure. We then discovered in a model of diet-induced obesity yielding equal adiposity in all study groups that whereas FcγRIIB(+/+) mice developed obesity-induced hypertension, FcγRIIB(-/-) mice were fully protected. Levels of CRP, the related pentraxin serum amyloid P component which is the CRP-equivalent in mice, and total IgG were unaltered by diet-induced obesity; FcγRIIB expression in endothelium was also unchanged. However, whereas IgG isolated from chow-fed mice had no effect, IgG from high-fat diet-fed mice inhibited endothelial NO synthase in cultured endothelial cells, and this was an FcγRIIB-dependent process. Thus, we have identified a novel role for FcγRIIB in the pathogenesis of obesity-induced hypertension, independent of processes regulating adiposity, and it may entail an IgG-induced attenuation of endothelial NO synthase function. Approaches targeting FcγRIIB may potentially offer new means to treat hypertension in obese individuals.
Collapse
Affiliation(s)
- Nathan C Sundgren
- From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas.
| | - Wanpen Vongpatanasin
- From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas
| | - Brigid-Meghan D Boggan
- From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas
| | - Keiji Tanigaki
- From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas
| | - Ivan S Yuhanna
- From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas
| | - Ken L Chambliss
- From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas
| | - Chieko Mineo
- From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas
| | - Philip W Shaul
- From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas
| |
Collapse
|
|
22
|
Effects of beta3-adrenoceptor activation on the interaction between adrenoceptors and angiotensin II receptors in apolipoprotein E knockout mouse lung. Eur J Pharmacol 2014; 742:75-80. [PMID: 25220245 DOI: 10.1016/j.ejphar.2014.09.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 09/03/2014] [Accepted: 09/04/2014] [Indexed: 11/20/2022]
Abstract
Hyperlipidemia can be harmful to the lung and β3-adrenoceptor agonist can improve lipid metabolism disorders. In this study, we aim to investigate the effects of β3-adrenoceptor activation on the interactions of adrenoceptors and angiotensin II receptors in aged apolipoprotein E gene knockout (ApoE(-/-)) mouse lung. Ten wild type C57BL/6J mice were included as normal control, 40 ApoE(-/-) mice were randomly divided into hyperlipidemia model (saline), low dose and high dose β3-adrenoceptor agonist and β3-adrenoceptor antagonist groups. After 26 weeks of high-fat diet, treatments were given for 12 weeks. Total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) were examined by an automatic biochemical analyzer. Quantitative real-time PCR and Western blot were used to analyze the mRNA and protein expression of α1A-, α1B-, α2A-, β1-, β2-, β3-adrenoceptors and angiotensin II type 1 and type 2 receptors in lung. We found that β3-adrenoceptor agonist could decrease TG, TC and LDL-C in aged ApoE(-/-) mice (P<0.01) and down-regulate the expressions of α1A-, α2A-adrenoceptors and angiotensin II type 1 receptor which were significantly increased in model mice (P<0.01, P<0.05). Compared with model mice, α1B-, β1-, β2-, β3-adrenoceptors and angiotensin II type 2 receptor expressions were increased in β3-adrenoceptor agonist-treat mice (P<0.01, P<0.05). These findings suggest that the expressions of adrenoceptors and angiotensin II receptors in lung are regulated towards adverse directions after taking β3-adrenoceptor agonist, which shows there are interactions between β3-adrenoceptor and other adrenoceptor subtypes and angiotensin II receptors. These interactions may play a protective role in lung under condition of hyperlipidemia.
Collapse
|
|
23
|
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.
Collapse
|
|
24
|
Houston M. The role of nutrition and nutraceutical supplements in the treatment of hypertension. World J Cardiol 2014; 6:38-66. [PMID: 24575172 PMCID: PMC3935060 DOI: 10.4330/wjc.v6.i2.38] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 10/22/2013] [Accepted: 12/17/2013] [Indexed: 02/06/2023] Open
Abstract
Vascular biology, endothelial and vascular smooth muscle and cardiac dysfunction play a primary role in the initiation and perpetuation of hypertension, cardiovascular disease and target organ damage. Nutrient-gene interactions and epigenetics are predominant factors in promoting beneficial or detrimental effects in cardiovascular health and hypertension. Macronutrients and micronutrients can prevent, control and treat hypertension through numerous mechanisms related to vascular biology. Oxidative stress, inflammation and autoimmune dysfunction initiate and propagate hypertension and cardiovascular disease. There is a role for the selected use of single and component nutraceutical supplements, vitamins, antioxidants and minerals in the treatment of hypertension based on scientifically controlled studies which complement optimal nutrition, coupled with other lifestyle modifications.
Collapse
Affiliation(s)
- Mark Houston
- Mark Houston, Hypertension Institute, Saint Thomas Medical Plaza, Nashville, TN 37205, United States
| |
Collapse
|
|
25
|
C-reactive protein and Hypertension. J Hum Hypertens 2013; 28:410-5. [DOI: 10.1038/jhh.2013.111] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Revised: 09/21/2013] [Accepted: 09/26/2013] [Indexed: 12/26/2022]
|
|
26
|
Houston M. Nutrition and nutraceutical supplements for the treatment of hypertension: part I. J Clin Hypertens (Greenwich) 2013; 15:752-7. [PMID: 24088285 PMCID: PMC8033896 DOI: 10.1111/jch.12188] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 07/19/2013] [Accepted: 07/21/2013] [Indexed: 12/16/2022]
Abstract
Vascular biology, endothelial and vascular smooth muscle, and cardiac dysfunction play a primary role in the initiation and perpetuation of hypertension, cardiovascular disease, and target organ damage. Nutrient-gene interactions and epigenetics are predominant factors in promoting beneficial or detrimental effects in cardiovascular health and hypertension. Macronutrients and micronutrients may be able to prevent, control, or treat hypertension through numerous mechanisms related to vascular biology or other mechanisms. Oxidative stress, inflammation, and autoimmune dysfunction are some of the primary factors that initiate and propagate hypertension and cardiovascular disease. The literature suggests that there may be a complementary role of single and component nutraceutical supplements, vitamins, antioxidants, and minerals in the treatment of hypertension when combined with optimal nutrition and other lifestyle modifications. However, many of these studies are small and do not have long-term follow-up for efficacy and safety. The role of these nutrition and nutraceutical supplements will require careful review and additional studies to determine their exact role in the management of hypertension.
Collapse
Affiliation(s)
- Mark Houston
- Department of Medicine, Vanderbilt University School of Medicine, Hypertension Institute of Nashville, Saint Thomas Medical Group and Health ServicesSaint Thomas HospitalNashvilleTN
| |
Collapse
|
|
27
|
Houston MC. The role of nutrition and nutraceutical supplements in the prevention and treatment of hypertension. ACTA ACUST UNITED AC 2013. [DOI: 10.2217/cpr.13.2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
|
|
28
|
Tanigaki K, Vongpatanasin W, Barrera JA, Atochin DN, Huang PL, Bonvini E, Shaul PW, Mineo C. C-reactive protein causes insulin resistance in mice through Fcγ receptor IIB-mediated inhibition of skeletal muscle glucose delivery. Diabetes 2013; 62:721-31. [PMID: 23069625 PMCID: PMC3581204 DOI: 10.2337/db12-0133] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Elevations in C-reactive protein (CRP) are associated with an increased risk of insulin resistance. Whether CRP plays a causal role is unknown. Here we show that CRP transgenic mice and wild-type mice administered recombinant CRP are insulin resistant. Mice lacking the inhibitory Fcγ receptor IIB (FcγRIIB) are protected from CRP-induced insulin resistance, and immunohistochemistry reveals that FcγRIIB is expressed in skeletal muscle microvascular endothelium and is absent in skeletal muscle myocytes, adipocytes, and hepatocytes. The primary mechanism in glucose homeostasis disrupted by CRP is skeletal muscle glucose delivery, and CRP attenuates insulin-induced skeletal muscle blood flow. CRP does not impair skeletal muscle glucose delivery in FcγRIIB(-/-) mice or in endothelial nitric oxide synthase knock-in mice with phosphomimetic modification of Ser1176, which is normally phosphorylated by insulin signaling to stimulate nitric oxide-mediated skeletal muscle blood flow and glucose delivery and is dephosphorylated by CRP/FcγRIIB. Thus, CRP causes insulin resistance in mice through FcγRIIB-mediated inhibition of skeletal muscle glucose delivery.
Collapse
MESH Headings
- Animals
- C-Reactive Protein/genetics
- C-Reactive Protein/metabolism
- Endothelium, Vascular/cytology
- Endothelium, Vascular/metabolism
- Glucose/metabolism
- Humans
- Immunohistochemistry
- Insulin/genetics
- Insulin/metabolism
- Insulin Resistance
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Microvessels/cytology
- Microvessels/metabolism
- Muscle, Skeletal/blood supply
- Muscle, Skeletal/cytology
- Muscle, Skeletal/metabolism
- Nitric Oxide Synthase Type III/antagonists & inhibitors
- Nitric Oxide Synthase Type III/genetics
- Nitric Oxide Synthase Type III/metabolism
- Organ Specificity
- Phosphorylation
- Protein Processing, Post-Translational
- Receptors, IgG/antagonists & inhibitors
- Receptors, IgG/genetics
- Receptors, IgG/metabolism
- Recombinant Proteins/metabolism
Collapse
Affiliation(s)
- Keiji Tanigaki
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Wanpen Vongpatanasin
- Hypertension Section, Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jose A. Barrera
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Dmitriy N. Atochin
- Cardiovascular Research Center and Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Paul L. Huang
- Cardiovascular Research Center and Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | | | - Philip W. Shaul
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Chieko Mineo
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
- Corresponding author: Chieko Mineo,
| |
Collapse
|
|
29
|
Ortiz RM, Mamalis A, Navar LG. Aldosterone Receptor Antagonism Reduces Urinary C-Reactive Protein Excretion in Angiotensin II-Infused, Hypertensive Rats. ACTA ACUST UNITED AC 2012; 3:184-91. [PMID: 20161115 DOI: 10.1016/j.jash.2009.01.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Elevated C-reactive protein (CRP) may contribute to elevated arterial pressure in Ang II-dependent hypertension. However, the in vivo effects of Ang II and of mineralocorticoid receptor (MR) antagonism on CRP during Ang II-dependent hypertension have not been examined. In addition, urinary CRP excretion as a method to monitor the progression of Ang II-induced inflammation has not been evaluated. METHODS Urine samples were collected from three groups (n = 10/group) of rats: 1) normotensive control, 2) angiotensin II infused (Ang II; 60 ng/min), and 3) Ang II + eplerenone (epl; 25 mg/d). A diet containing epl (0.1 %) was provided after 1 week of Ang II infusion. RESULTS After 28 d, Ang II increased SBP from 136 +/- 5 to 207 +/- 8 mmHg; this response in SBP was not altered following MR antagonism (215 +/- 6 mmHg). Ang II-infusion increased plasma CRP from 14 +/- 2 to 26 +/- 3 mug/mL and increased urinary CRP excretion nearly 8-fold (143 +/- 26 vs 1102 +/- 115 ng/d). Treatment with eplerenone reduced plasma CRP by 25 % and urinary immunoreactive CRP (irCRP) by 34 % in Ang II-infused rats suggesting that aldosterone contributes to the CRP-associated inflammatory response in Ang II-dependent hypertension. CONCLUSIONS The increase in SBP preceded the increase in irCRP excretion by at least 4 days suggesting that CRP does not significantly contribute to increased arterial blood pressure in Ang II-dependent hypertension. The blockade of MR reduced plasma CRP and urinary irCRP excretion demonstrating the contribution of aldosterone to the Ang II-induced generation of CRP. Furthermore, urinary CRP may serve as a non-invasive index for monitoring cardiovascular inflammation during hypertension.
Collapse
Affiliation(s)
- Rudy M Ortiz
- Division of Natural Sciences, University of California, Merced CA
| | | | | |
Collapse
|
|
30
|
|
|
31
|
Nolan RP, Floras JS, Ahmed L, Harvey PJ, Hiscock N, Hendrickx H, Talbot D. Behavioural modification of the cholinergic anti-inflammatory response to C-reactive protein in patients with hypertension. J Intern Med 2012; 272:161-9. [PMID: 22292421 DOI: 10.1111/j.1365-2796.2012.02523.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES A central hypothesis of the cholinergic anti-inflammatory reflex model is that innate immune activity is inhibited by the efferent vagus. We evaluated whether changes in markers of tonic or reflex vagal heart rate modulation following behavioural intervention were associated inversely with changes in high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6). DESIGN Subjects diagnosed with hypertension (n = 45, age 35-64 years, 53% women) were randomized to an 8-week protocol of behavioural neurocardiac training (with heart rate variability biofeedback) or autogenic relaxation. Assessments before and after intervention included pro-inflammatory factors (hsCRP, IL-6), markers of vagal heart rate modulation [RR high-frequency (HF) power within 0.15-0.40 Hz, baroreflex sensitivity and RR interval], conventional measures of lipoprotein cholesterol and 24-h ambulatory systolic and diastolic blood pressure. RESULTS Changes in hsCRP and IL-6 were not associated with changes in lipoprotein cholesterol or blood pressure. After adjusting for anti-inflammatory drugs and confounding factors, changes in hsCRP related inversely to changes in HF power (β = -0.25±0.1, P = 0.02), baroreflex sensitivity (β = -0.33±0.7, P = 0.04) and RR interval (β = -0.001 ± 0.0004, P = 0.02). Statistically significant relationships were not observed for IL-6. CONCLUSIONS Changes in hsCRP were consistent with the inhibitory effect of increased vagal efferent activity on pro-inflammatory factors predicted by the cholinergic anti-inflammatory reflex model. Clinical trials for patients with cardiovascular dysfunction are warranted to assess whether behavioural interventions can contribute independently to the chronic regulation of inflammatory activity and to improved clinical outcomes.
Collapse
Affiliation(s)
- R P Nolan
- University Health Network and University of Toronto, ON, Canada.
| | | | | | | | | | | | | |
Collapse
|
|
32
|
den Hertog HM, van der Worp HB, van Gemert HMA, van Gijn J, Koudstaal PJ, Dippel DWJ. Effects of high-dose paracetamol on blood pressure in acute stroke. Acta Neurol Scand 2012; 125:265-71. [PMID: 21649610 DOI: 10.1111/j.1600-0404.2011.01529.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Early administration of paracetamol may improve outcome of patients with acute stroke and a baseline body temperature of 37°C or above by lowering body temperature and preventing fever. Besides its antipyretic effects, paracetamol may affect blood pressure through cyclooxygenase-2 inhibition. We therefore aimed to assess the effect of high-dose paracetamol on blood pressure in patients with acute stroke. METHODS We analyzed data of 540 patients admitted within 24 h of stroke onset who were randomized to treatment with either paracetamol (6 g daily) or placebo. Blood pressures were measured at 12, 24, and 48 h from the start of treatment. Changes in blood pressure from baseline in the two treatment groups and corresponding 95% confidence intervals (CI) were calculated with linear regression analysis. Adjustments for potential confounders were made with a multiple linear regression model. RESULTS Treatment with high-dose paracetamol was associated with a significant reduction in systolic blood pressure of 4.5 mm Hg (95% CI 0.6-8.5) at 12 h from the start of treatment. This effect was no longer present after 24 and 48 h. CONCLUSION High-dose paracetamol reduces not only body temperature but also systolic blood pressure in the first 12 h after start of treatment. Both effects may improve functional outcome after stroke, but this needs further study.
Collapse
Affiliation(s)
- H M den Hertog
- Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
| | | | | | | | | | | |
Collapse
|
|
33
|
Masiha S, Sundström J, Lind L. Inflammatory markers are associated with left ventricular hypertrophy and diastolic dysfunction in a population-based sample of elderly men and women. J Hum Hypertens 2012; 27:13-7. [DOI: 10.1038/jhh.2011.113] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|
|
34
|
Abstract
Caveolae are a specialized subset of lipid domains that are prevalent on the plasma membrane of endothelial cells. They compartmentalize signal transduction molecules which regulate multiple endothelial functions including the production of nitric oxide (NO) by the caveolae resident enzyme endothelial NO synthase (eNOS). eNOS is one of the three isoforms of the NOS enzyme which generates NO upon the conversion of L-arginine to L-citrulline and it is regulated by multiple mechanisms. Caveolin negatively impact eNOS activity through direct interaction with the enzyme. Circulating factors known to modify cardiovascular disease risk also influence the activity of the enzyme. In particular, high density lipoprotein cholesterol (HDL) maintains the lipid environment in caveolae, thereby promoting the retention and function of eNOS in the domain and it also causes direct activation of eNOS via scavenger receptor class B, Type I (SR-BI)-induced kinase signaling. Estrogen binding to estrogen receptors (ER) in caveolae also activates eNOS and this occurs through G protein coupling and kinase activation. Discrete domains within SR-BI and ER mediating signal initiation in caveolae have been identified. Counteracting the promodulatory actions of HDL and estrogen, C-reactive protein (CRP) antagonizes eNOS through FcγRIIB, which is the sole inhibitory receptor for IgG. Through their actions on eNOS, estrogen and CRP also regulate endothelial cell growth and migration. Thus, signaling events in caveolae invoked by known circulating cardiovascular disease risk factors have major impact on eNOS and endothelial cell phenotypes of importance to cardiovascular health and disease.
Collapse
Affiliation(s)
- Chieko Mineo
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | | |
Collapse
|
|
35
|
Liu F, Chen HY, Huang XR, Chung ACK, Zhou L, Fu P, Szalai AJ, Lan HY. C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes. Diabetologia 2011; 54:2713-23. [PMID: 21744073 DOI: 10.1007/s00125-011-2237-y] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Accepted: 06/08/2011] [Indexed: 02/05/2023]
Abstract
AIMS/HYPOTHESIS Although C-reactive protein (CRP) has been implicated as a risk factor in diabetes, its pathogenic importance in diabetic kidney disease (DKD) remains unclear. The present study investigated the potential role of CRP in DKD. METHODS Diabetes was induced by streptozotocin in human CRP transgenic and wild-type mice for assessment of kidney injury at 24 weeks by real-time PCR, immunohistochemistry and western blot analysis. In vitro, the pathogenic effect of CRP was investigated using human kidney tubular epithelial cells cultured with high glucose and/or CRP. RESULTS We found that CRP transgenic mice developed much more severe diabetic kidney injury than wild-type mice, as indicated by a significant increase in urinary albumin excretion and kidney injury molecule-1 abundance, enhanced infiltration of macrophages and T cells, and upregulation of pro-inflammatory cytokines (IL-1β, TNFα) and extracellular matrix (collagen I, III and IV). Enhanced renal inflammation and fibrosis in CRP transgenic mice was associated with upregulation of CRP receptor, CD32a, and over-activation of the TGF-β/SMAD and nuclear factor κB signalling pathways. In vitro, CRP significantly upregulated pro-inflammatory cytokines (IL-1β, TNFα, monocyte chemoattractant protein-1 [MCP-1]) and pro-fibrotic growth factors (TGF-β1, connective tissue growth factor [CTGF]) via CD32a/64. CRP was induced by high glucose, which synergistically promoted high glucose-mediated renal inflammation and fibrosis. CONCLUSIONS/INTERPRETATION CRP is not only a biomarker, but also a mediator in DKD. Enhanced activation of TGF-β/SMAD and nuclear factor κB signalling pathways may be the mechanisms by which CRP promotes renal inflammation and fibrosis under diabetic conditions.
Collapse
Affiliation(s)
- F Liu
- Department of Nephrology, West China Hospital of Sichuan University, Chengdu, People's Republic of China
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Sundgren NC, Zhu W, Yuhanna IS, Chambliss KL, Ahmed M, Tanigaki K, Umetani M, Mineo C, Shaul PW. Coupling of Fcγ receptor I to Fcγ receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function. Circ Res 2011; 109:1132-40. [PMID: 21940940 DOI: 10.1161/circresaha.111.254573] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
RATIONALE Elevations in C-reactive protein (CRP) are associated with increased cardiovascular disease risk and endothelial dysfunction. CRP antagonizes endothelial nitric oxide synthase (eNOS) through processes mediated by the IgG receptor Fcγ receptor IIB (FcγRIIB), its immunoreceptor tyrosine-based inhibitory motif, and SH2 domain-containing inositol 5'-phosphatase 1. In mice, CRP actions on eNOS blunt carotid artery re-endothelialization. OBJECTIVE How CRP activates FcγRIIB in endothelium is not known. We determined the role of Fcγ receptor I (FcγRI) and the basis for coupling of FcγRI to FcγRIIB in endothelium. METHODS AND RESULTS In cultured endothelial cells, FcγRI-blocking antibodies prevented CRP antagonism of eNOS, and CRP activated Src via FcγRI. CRP-induced increases in FcγRIIB immunoreceptor tyrosine-based inhibitory motif phosphorylation and SH2 domain-containing inositol 5'-phosphatase 1 activation were Src-dependent, and Src inhibition prevented eNOS antagonism by CRP. Similar processes mediated eNOS antagonism by aggregated IgG used to mimic immune complex. Carotid artery re-endothelialization was evaluated in offspring from crosses of CRP transgenic mice (TG-CRP) with either mice lacking the γ subunit of FcγRI (FcRγ(-/-)) or FcγRIIB(-/-) mice. Whereas re-endothelialization was impaired in TG-CRP vs wild-type, it was normal in both FcRγ(-/-); TG-CRP and FcγRIIB(-/-); TG-CRP mice. CONCLUSIONS CRP antagonism of eNOS is mediated by the coupling of FcγRI to FcγRIIB by Src kinase and resulting activation of SH2 domain-containing inositol 5'-phosphatase 1, and consistent with this mechanism, both FcγRI and FcγRIIB are required for CRP to blunt endothelial repair in vivo. Similar mechanisms underlie eNOS antagonism by immune complex. FcγRI and FcγRIIB may be novel therapeutic targets for preventing endothelial dysfunction in inflammatory or immune complex-mediated conditions.
Collapse
Affiliation(s)
- Nathan C Sundgren
- Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Jialal I, Devaraj S, Siegel D. CRP induces hypertension in animal models: homo sapiens says NO. Hypertens Res 2011; 34:801-2. [DOI: 10.1038/hr.2011.59] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|
|
38
|
Li X, Yang G, Zhao G, Wu B, Edin ML, Zeldin DC, Wang DW. Rosuvastatin attenuates the elevation in blood pressure induced by overexpression of human C-reactive protein. Hypertens Res 2011; 34:869-75. [PMID: 21562509 DOI: 10.1038/hr.2011.44] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
C-reactive protein (CRP) has been shown to function as an inflammatory factor to induce endothelial dysfunction and hypertension in rats. The anti-inflammatory effects of statins suggest that they may attenuate CRP-induced endothelial dysfunction and hypertension in Sprague-Dawley rats. Male Sprague-Dawley rats were injected with an adeno-associated virus (AAV) to induce overexpression of human CRP (AAV-hCRP) or green fluorescent protein (GFP) control (AAV-GFP). At 2 months after injection, rats were administered rosuvastatin by daily oral gavage (10 mg kg(-1)) for 2 additional months. Rosuvastatin administration attenuated the increased blood pressure and loss of vascular endothelial nitric oxide synthase expression in AAV-hCRP-treated rats, and N-nitro-L-arginine methyl ester blocked its hypotensive effect. Rosuvastatin also activated phosphoinositide 3-kinases/Akt, and inhibited Rho kinase activity in aorta. Rosuvastatin reduced the production of reactive oxygen species through downregulation of nicotinamide adenine dinucleotide phosphate oxidase subunits, p22 phox and gp91 phox, and upregulation of superoxide dismutase 1 expression. Rosuvastatin attenuated the increase in blood pressure in AAV-hCRP-treated rats through endothelial protection and antioxidant effects. Our data reveals a novel mechanism through which statins may lower blood pressure.
Collapse
Affiliation(s)
- Xuguang Li
- Departments of Internal Medicine, The Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Affiliation(s)
- Jisun Oh
- Division of Endocrinology and Metabolism, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
| | | | | |
Collapse
|
|
40
|
Abstract
Hypertension is associated with vascular changes characterised by remodelling, endothelial dysfunction and hyperreactivity. Cellular processes underlying these perturbations include altered vascular smooth muscle cell growth and apoptosis, fibrosis, hypercontractility and calcification. Inflammation, associated with macrophage infiltration and increased expression of redox-sensitive pro-inflammatory genes, also contributes to vascular remodelling. Many of these features occur with ageing, and the vascular phenotype in hypertension is considered a phenomenon of ‘premature vascular ageing’. Among the many factors involved in the hypertensive vascular phenotype, angiotensin II (Ang II) is especially important. Ang II, previously thought to be the sole effector of the renin–angiotensin system (RAS), is converted to smaller peptides [Ang III, Ang IV, Ang-(1-7)] that are biologically active in the vascular system. Another new component of the RAS is the (pro)renin receptor, which signals through Ang-II-independent mechanisms and might influence vascular function. Ang II mediates effects through complex signalling pathways on binding to its G-protein-coupled receptors (GPCRs) AT1R and AT2R. These receptors are regulated by the GPCR-interacting proteins ATRAP, ARAP1 and ATIP. AT1R activation induces effects through the phospholipase C pathway, mitogen-activated protein kinases, tyrosine kinases/phosphatases, RhoA/Rhokinase and NAD(P)H-oxidase-derived reactive oxygen species. Here we focus on recent developments and new research trends related to Ang II and the RAS and involvement in the hypertensive vascular phenotype.
Collapse
|
|
41
|
|
|
42
|
|
|
43
|
Pravenec M, Kajiya T, Zídek V, Landa V, Mlejnek P, Simáková M, Silhavý J, Malínská H, Oliyarnyk O, Kazdová L, Fan J, Wang J, Kurtz TW. Effects of human C-reactive protein on pathogenesis of features of the metabolic syndrome. Hypertension 2011; 57:731-7. [PMID: 21357282 DOI: 10.1161/hypertensionaha.110.164350] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Major controversy exists as to whether increased C-reactive protein (CRP) contributes to individual components of the metabolic syndrome or is just a secondary response to inflammatory disease processes. We measured blood pressure and metabolic phenotypes in spontaneously hypertensive rats (SHRs) in which we transgenically expressed human CRP in the liver under control of the apolipoprotein E promoter. In transgenic SHRs, serum levels of human CRP approximated the endogenous levels of CRP normally found in the rat. Systolic and diastolic blood pressures measured by telemetry were 10 to 15 mm Hg greater in transgenic SHRs expressing human CRP than in SHR controls (P<0.01). During oral glucose tolerance testing, transgenic SHRs exhibited hyperinsulinemia compared with controls (insulin area under the curve: 36±7 versus 8±2 nmol/L per 2 hours, respectively; P<0.05). Transgenic SHRs also exhibited resistance to insulin stimulated glycogenesis in skeletal muscle (174±18 versus 278±32 nmol of glucose per gram per 2 hours; P<0.05), hypertriglyceridemia (0.84±0.05 versus 0.64±0.03 mmol/L; P<0.05), reduced serum adiponectin (2.4±0.3 versus 4.3±0.6 mmol/L; P<0.05), and microalbuminuria (200±35 versus 26±5 mg of albumin per gram of creatinine, respectively; P<0.001). Transgenic SHRs had evidence of inflammation and oxidative tissue damage with increased serum levels of interleukin 6 (36.4±5.2 versus 18±1.7 pg/mL; P<0.005) and increased hepatic and renal thiobarbituric acid reactive substances (1.2±0.09 versus 0.8±0.07 and 1.5±0.1 versus 1.1±0.05 nmol/L per milligram of protein, respectively; P<0.01), suggesting that oxidative stress may be mediating adverse effects of increased human CRP. These findings are consistent with the hypothesis that increased CRP is more than just a marker of inflammation and can directly promote multiple features of the metabolic syndrome.
Collapse
Affiliation(s)
- Michal Pravenec
- Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Abstract
Current evidence suggests a role for obstructive sleep apnea (OSA) in the development of cardiovascular disorders. However, obesity is an active confounder in this relationship. OSA and obesity share similar pathophysiologic mechanisms potentially leading to cardiovascular disorders. Presence of OSA in obese patients may further contribute to adverse cardiovascular outcomes when compared with each condition in isolation. In this review the authors explore the complex relationship between OSA and obesity (and nonobese subjects) in the development of cardiovascular disorders.
Collapse
|
|
45
|
C-reactive protein gene variant and the human left ventricular growth response to exercise: data from The LARGE Heart Study. J Cardiovasc Pharmacol 2010; 55:26-9. [PMID: 19834334 DOI: 10.1097/fjc.0b013e3181c37d2d] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Increased levels of C-reactive protein (CRP) are associated with left ventricular (LV) hypertrophy. This association may be causal (either directly or indirectly) or simply a confounder resulting from the recognized relationship between CRP and vascular disease. We attempted to clarify this issue, by assessing the association of a variant of the CRP gene with exercise-induced left ventricular hypertrophy in young healthy males: homozygosity for the T (rather than C) allele of the CRP +1444C>T gene variant is associated with serum CRP levels which are 0.68 mg/L higher than carriers of the C allele. METHODS AND RESULTS LV mass was measured using cardiovascular magnetic resonance in 301 army recruits before and after an identical 12-week physical training program. Subjects were genotyped for the CRP +1444C>T gene variant. LV mass was 164.25 +/-24.52 g at entry and increased with training (+3.77 +/- 10.77 g). This increase was greatest among those homozygous for the rare T allele (+8.17 6 12.09 vs. +3.37 6 10.58 for TT genotype vs. C-allele carriers respectively, P = 0.033). CONCLUSIONS CRP genotype is associated with a greater LV growth to exercise, supporting a causal association between CRP and LV growth. Whether such an association might be directly mediated or results from alterations in phenotypes which themselves drive LV growth (for instance, altered arterial compliance) is not clear.
Collapse
|
|
46
|
Zhang R, Zhang YY, Huang XR, Wu Y, Chung AC, Wu EX, Szalai AJ, Wong BC, Lau CP, Lan HY. C-Reactive Protein Promotes Cardiac Fibrosis and Inflammation in Angiotensin II–Induced Hypertensive Cardiac Disease. Hypertension 2010; 55:953-60. [DOI: 10.1161/hypertensionaha.109.140608] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Rongxin Zhang
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Yuan Yuan Zhang
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Xiao R. Huang
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Yin Wu
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Arthur C.K. Chung
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Ed Xuekui Wu
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Alexander J. Szalai
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Benjamin C.Y. Wong
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Chu-Pak Lau
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| | - Hui Y. Lan
- From the Departments of Medicine (R.Z., Y.Y.Z., X.R.H., A.C.K.C., B.C.Y.W., C.-P.L., H.Y.L.) and Electrical and Electronic Engineering (Y.W., E.X.W.), University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences (X.R.H., A.C.K.C., H.Y.L.), Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Medicine (A.J.S.), University of Alabama at Birmingham, Birmingham, Ala
| |
Collapse
|
|
47
|
Lemarié CA, Schiffrin EL. The angiotensin II type 2 receptor in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 2009; 11:19-31. [PMID: 19861349 DOI: 10.1177/1470320309347785] [Citation(s) in RCA: 124] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Angiotensin II (Ang II) is considered the major final mediator of the renin-angiotensin system. The actions of Ang II have been implicated in many cardiovascular conditions, such as hypertension, atherosclerosis, coronary heart disease, restenosis, and heart failure. Ang II can act through two different receptors: Ang II type 1 (AT(1)) receptor and Ang II type 2 (AT(2)) receptor. The AT(1) receptor is ubiquitously expressed in the cardiovascular system and mediates most of the physiological and pathophysiological actions of Ang II. The AT(2) receptor is highly expressed in the developing foetus, but its expression is very low in the cardiovascular system of the normal adult. Expression of the AT(2) receptor can be modulated by pathological states associated with tissue remodelling or inflammation such as hypertension, atherosclerosis, and myocardial infarction. The precise role of the AT(2) receptor remains under debate. However, it appears that the AT(2) receptor plays a vasodilatory role, and may be enhanced as a countervailing mechanism in cardiac hypertrophy, and in presence of vascular injury in hypertension and atherosclerosis. Signalling pathways induced by the stimulation of the AT(2) receptor are poorly understood, but three main mechanisms have been described: (a) activation of protein phosphatases causing protein dephosphorylation; (b) activation of bradykinin/nitric oxide/cyclic guanosine 3',5'-monophosphate pathway; and (c) stimulation of phospholipase A(2) and release of arachidonic acid. Vasodilatory effects of the AT(2) receptor, probably the only well-established role of the AT(2) receptor, have been attributed to the second of these mechanisms. The participation of the AT(2) receptor in cardiovascular remodelling and inflammation is more controversial. In vitro, AT(2) receptor stimulation clearly inhibits cardiac and vascular smooth muscle growth and proliferation, and stimulates apoptosis. In vivo, the situation is less clear, and depending on the studies, the AT(2) receptor appears to be required for cardiac hypertrophic growth or contrariwise, the AT(2) receptor has demonstrated no effects on cardiac hypertrophy. Similar controversial findings have been reported in atherosclerosis. Here we discuss the role of the AT(2) receptor on cardiovascular structure and disease, and the signalling pathways induced by its activation.
Collapse
Affiliation(s)
- Catherine A Lemarié
- Hypertension and Vascular Research Unit, Lady Davis Institute for Medical Research, Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, QC, Canada
| | | |
Collapse
|
|
48
|
Abstract
Obstructive sleep apnoea (OSA) is a common disorder in which repetitive apnoeas expose the cardiovascular system to cycles of hypoxia, exaggerated negative intrathoracic pressure, and arousals. These noxious stimuli can, in turn, depress myocardial contractility, activate the sympathetic nervous system, raise blood pressure, heart rate, and myocardial wall stress, depress parasympathetic activity, provoke oxidative stress and systemic inflammation, activate platelets, and impair vascular endothelial function. Epidemiological studies have shown significant independent associations between OSA and hypertension, coronary artery disease, arrhythmias, heart failure, and stroke. In randomised trials, treating OSA with continuous positive airway pressure lowered blood pressure, attenuated signs of early atherosclerosis, and, in patients with heart failure, improved cardiac function. Current data therefore suggest that OSA increases the risk of developing cardiovascular diseases, and that its treatment has the potential to diminish such risk. However, large-scale randomised trials are needed to determine, definitively, whether treating OSA improves cardiovascular outcomes.
Collapse
Affiliation(s)
- T Douglas Bradley
- Sleep Research Laboratory of the Toronto Rehabilitation Institute, Toronto, Canada
| | | |
Collapse
|
|
49
|
Proinflammation and hypertension: a population-based study. Mediators Inflamm 2008; 2008:619704. [PMID: 19125204 PMCID: PMC2612739 DOI: 10.1155/2008/619704] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2008] [Revised: 10/03/2008] [Accepted: 11/08/2008] [Indexed: 12/11/2022] Open
Abstract
There is evidence that proinflammation may be linked to the development of hypertension (HT). We examined the association of both the interleukin-1 beta (IL-1β) and the interleukin 1-receptor antagonist (IL-1ra) with future blood pressure (BP) and HT occurrence (BP ≥ 140/90 mmHg, or antihypertensive drug) in a population-based prospective study. Our study consisted of 396 (147 men and 249 women) middle-aged, baseline apparently healthy, normotensive subjects participating in a 6.5-year follow-up study. Subjects with high-sensitivity CRP (hs-CRP) < 10 mg/L were excluded at the initial visit. At follow-up, the occurrence of HT was 32%. The levels of baseline IL-1β and IL-1ra were significantly higher for subjects who developed HT during the follow-up than for those who did not (IL-1β; 0.67 ± 0.62 pg/mL versus 0.56 ± 0.32 pg/mL, P = .020 and IL-1ra; 184 ± 132 pg/mL versus 154 ± 89 pg/mL, P = .007). After adjustments for age, follow-up time, sex, baseline systolic BP, and BMI, our results confirm a statistically significant (P = .036) linear association between the quartiles of IL-1β and change of systolic BP during the study. After adjustments for age, follow-up time, sex, and BMI, our results also show a linear association between incident HT and the quartiles of IL-1ra. (P = .026). These results provide evidence that proinflammation may precede BP elevation and HT.
Collapse
|
|
50
|
Jialal I, Verma S, Devaraj S. Inhibition of endothelial nitric oxide synthase by C-reactive protein: clinical relevance. Clin Chem 2008; 55:206-8. [PMID: 19095724 DOI: 10.1373/clinchem.2008.119206] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
|