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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/E103    most recent 00752.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Whaley-Connell, A. Articles by Sowers, J. R. PubMed PubMed Citation Articles by Whaley-Connell, A. Articles by Sowers, J. R.

Effect of renin inhibition and AT₁R blockade on myocardial remodeling in the transgenic Ren2 rat

¹The University of Missouri School of Medicine, Departments of Medicine and ²Pharmacology and Physiology, ³Diabetes and Cardiovascular Center of Excellence; ⁴Harry S. Truman Veterans Affairs Medical Center, Columbia, Missouri; and ⁵Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Submitted 30 November 2007 ; accepted in final form 28 April 2008

Angiotensin II (Ang II) stimulation of the Ang type 1 receptor (AT₁R) facilitates myocardial remodeling through NADPH oxidase-mediated generation of oxidative stress. Components of the renin-angiotensin system constitute an autocrine/paracrine unit in the myocardium, including renin, which is the rate-limiting step in the generation of Ang II. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo renin inhibition and/or AT₁R blockade in a rodent model of chronically elevated tissue Ang II levels, the transgenic (mRen2)27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, and cardiovascular damage. Young (6- to 7-wk-old) heterozygous (+/–) male Ren2 and age-matched Sprague-Dawley rats were treated with the renin inhibitor aliskiren, which has high preferential affinity for human and mouse renin, an AT₁R blocker, irbesartan, or placebo for 3 wk. Myocardial NADPH oxidase activity and immunostaining for NADPH oxidase subunits and 3-nitrotyrosine were evaluated and remodeling changes assessed by light and transmission electron microscopy. Blood pressure, myocardial NADPH oxidase activity and subunit immunostaining, 3-nitrotyrosine, perivascular fibrosis, mitochondrial content, and markers of activity were significantly increased in Ren2 compared with SD littermates. Both renin inhibition and blockade of the AT₁R significantly attenuated cardiac functional and structural alterations, although irbesartan treatment resulted in greater reductions of both blood pressure and markers of oxidative stress. Collectively, these data suggest that both reduce changes driven, in part, by Ang II-mediated increases in NADPH oxidase and, in part, increases in blood pressure.

cardiac remodeling; reduced nicotinamide adenine dinucleotide phosphate oxidase; oxidative stress