| Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling. | |
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MedLine Citation:
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PMID: 17494996 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine, and NADPH oxidase (NOX) subunits (gp91(phox) recently renamed NOX2, p22(phox), Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX. |
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Authors:
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Sameer Stas; Adam Whaley-Connell; Javad Habibi; Lama Appesh; Melvin R Hayden; Poorna R Karuparthi; Mahnaz Qazi; E Matthew Morris; Shawna A Cooper; C Daniel Link; Craig Stump; Meredith Hay; Carlos Ferrario; James R Sowers |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2007-05-10 |
Journal Detail:
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Title: Endocrinology Volume: 148 ISSN: 0013-7227 ISO Abbreviation: Endocrinology Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-07-19 Completed Date: 2007-09-11 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
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Languages: eng Pagination: 3773-80 Citation Subset: AIM; IM |
Affiliation:
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Division of Endocrinology, University of Missouri School of Medicine, Columbia, Missouri 65212, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aldosterone Antagonists
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pharmacology* Animals Animals, Genetically Modified Blood Pressure / physiology Cardiomegaly / drug therapy*, metabolism, pathology Chronic Disease Fibrosis Magnetic Resonance Imaging Male Microscopy, Electron, Transmission Mitochondria / metabolism, pathology, ultrastructure Myocardium / metabolism, pathology Myocytes, Cardiac / metabolism, pathology, ultrastructure NADPH Oxidase / metabolism* Oxidative Stress / physiology Rats Rats, Sprague-Dawley Receptors, Mineralocorticoid / antagonists & inhibitors*, metabolism Renin / genetics, metabolism Renin-Angiotensin System / drug effects, physiology Spironolactone / pharmacology* Ventricular Dysfunction, Left / drug therapy, metabolism, pathology Ventricular Remodeling / drug effects*, physiology |
| Grant Support | |
ID/Acronym/Agency:
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HL-51952/HL/NHLBI NIH HHS; P01 HL-51952/HL/NHLBI NIH HHS; R01 HL73101-01A1/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Aldosterone Antagonists; 0/Receptors, Mineralocorticoid; 0/Ren2 protein, mouse; 52-01-7/Spironolactone; EC 1.6.3.1/NADPH Oxidase; EC 3.4.23.15/Renin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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