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dc.contributor.authorStas, Sameereng
dc.contributor.authorWhaley-Connell, Adam T.eng
dc.contributor.authorHabibi, Javad, 1947-eng
dc.contributor.authorAppesh, Lamaeng
dc.contributor.authorHayden, Melvineng
dc.contributor.authorKaruparthi, Poorna R.eng
dc.contributor.authorQazi, Mahnazeng
dc.contributor.authorMorris, E. Mattheweng
dc.contributor.authorCooper, Shawna A.eng
dc.contributor.authorLink, C. Danieleng
dc.contributor.authorStump, Craigeng
dc.contributor.authorHay, Mereditheng
dc.contributor.authorFerrario, Carlos M.eng
dc.contributor.authorSowers, James R. (James Russell), 1942-eng
dc.descriptiondoi: 10.1210/en.2006-1691eng
dc.description.abstractThe 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.eng
dc.description.sponsorshipThis 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.eng
dc.identifier.citationMineralocorticoid 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.eng
dc.relation.ispartofEndocrinology publications (MU)eng
dc.relation.ispartofcommunityUniversity of Missouri-Columbia. School of Medicine. Department of Internal Medicine. Division of Endocrinologyeng
dc.source.harvestedEndocrinology Web siteeng
dc.subject.lcshRenin-angiotensin systemeng
dc.subject.lcshOxidative stresseng
dc.subject.lcshVentricular remodelingeng
dc.subject.lcshHeart -- Hypertrophyeng
dc.titleMineralocorticoid Receptor Blockade Attenuates Chronic Overexpression of the Renin-Angiotensin- Aldosterone System Stimulation of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase and Cardiac Remodelingeng

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