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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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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dc.contributor.author Stas, Sameer
dc.contributor.author Whaley-Connell, Adam T.
dc.contributor.author Habibi, Javad, 1947-
dc.contributor.author Appesh, Lama
dc.contributor.author Hayden, Melvin
dc.contributor.author Karuparthi, Poorna R.
dc.contributor.author Qazi, Mahnaz
dc.contributor.author Morris, E. Matthew
dc.contributor.author Cooper, Shawna A.
dc.contributor.author Link, C. Daniel
dc.contributor.author Stump, Craig
dc.contributor.author Hay, Meredith
dc.contributor.author Ferrario, Carlos M.
dc.contributor.author Sowers, James R. (James Russell), 1942-
dc.date.accessioned 2010-09-15T14:34:17Z
dc.date.available 2010-09-15T14:34:17Z
dc.date.issued 2007-08
dc.identifier.citation Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin- Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling. Endocrinology, 148(8), 3773-3780. en_US
dc.identifier.issn 0013-7227/07/$15.00/0
dc.identifier.uri http://hdl.handle.net/10355/8499
dc.description doi: 10.1210/en.2006-1691
dc.description.abstract 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 (gp91phox recently renamed NOX2, p22phox, 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. en_US
dc.description.sponsorship This research was supported by National Institutes of Health (NIH) Grants R01 HL73101-01A1 (to J.R.S.) and P01 HL-51952 (to C.F.), the Veterans Affairs Merit System (0018) (to J.R.S.), and Advanced Research Career Development (to C.S.). Male transgenic Ren2 rats and male Sprague-Dawley controls were kindly provided by C.F. through the Transgenic Core Facility supported in part by NIH Grant HL-51952.
dc.language.iso en_US en_US
dc.publisher Endocrinology en_US
dc.relation.ispartof Endocrinology publications (MU) en_US
dc.subject.lcsh Renin-angiotensin system en_US
dc.subject.lcsh Oxidative stress en_US
dc.subject.lcsh Ventricular remodeling en_US
dc.subject.lcsh Heart -- Hypertrophy
dc.title Mineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin- Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodeling en_US
dc.type Article en_US
dc.source.harvested Endocrinology Web site en_US
dc.relation.ispartofcommunity University of Missouri-Columbia. School of Medicine. Department of Internal Medicine. Division of Endocrinology


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