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Submitted on December 18, 2006
Accepted on April 27, 2007
University of Missouri School of Medicine, Divisions of Endocrinology and Nephrology, Diabetes and Cardiovascular Lab, and Harry S. Truman VA Medical Center, The University of Arizona Department of Medicine, University of Iowa , Wake Forest University School of Medicine
* To whom correspondence should be addressed. E-mail: sowersj{at}health.missouri.edu.
Renin-angiotensin-aldosterone system (RAAS) contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Ang-II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via 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 mineralcorticoid receptor (MR) blockade in a rodent model of chronically elevated tissue RAAS, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6-7 week old) male Ren2 and age-matched Sprague-Dawley (SD) rats were treated with spironolactone or placebo for three weeks. Heart tissue reactive oxygen species (ROS), immunohistochemical (IHC) 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 MRI, transmission electron microscopy (TEM), and light microscopy. Significant increases in Ren2 septal wall thickness (cine MRI) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and TEM. Although there was no significant reduction in systolic blood pressure (SBP), significant improvements were seen with MR blockade on ROS formation and NADPH oxidase subunits (each p<0.05). Collectively, these data suggest that MR blockade, independent of SBP reduction, improves cardiac oxidative stress induced structural and functional changes, which are driven, in part, by AT1R-mediated increases in NADPH oxidase.
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