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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

Divisions of Endocrinology (S.S., M.R.H., J.R.S.) and Nephrology (A.W.-C.), Diabetes and Cardiovascular Lab (S.S., A.W.-C., J.H., L.A., M.Q., E.M.M., S.A.C., J.R.S.), University of Missouri School of Medicine (S.S., A.W.-C., J.H., L.A., M.R.H., P.R.K., M.Q., E.M.M., S.A.C., J.R.S.), Columbia, Missouri 65212; Harry S. Truman Veterans Administration Medical Center (A.W.-C., J.H., L.A., J.R.S.), Columbia, Missouri 65201; Department of Medicine (C.S., C.D.L), The University of Arizona, Tucson, Arizona 85721; University of Iowa (M.H.), Iowa City, Iowa 52242; and Wake Forest University School of Medicine (C.F.), Winston-Salem, North Carolina 27157

Address all correspondence and requests for reprints to: James R. Sowers, M.D., F.A.C.E., F.A.C.P., F.A.H.A., Professor of Medicine, Physiology and Pharmacology, University of Missouri-Columbia, Health Sciences Center, MA410, DC043.00, Columbia, Missouri 65212. E-mail: sowersj{at}health.missouri.edu.

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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