Submitted on November 30, 2007
Accepted on April 28, 2008
Effect of Renin Inhibition and AT1R Blockade on Myocardial Remodeling in the Transgenic Ren2 Rat
Adam Whaley-Connell1, Javad Habibi2, Shawna A Cooper2, Vincent G DeMarco3, Melvin R Hayden2, Craig S Stump4, Daniel Link4, Carlos Ferrario5, and James R Sowers2*
1 Internal Medicine, Division of Nephrology, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
2 Internal Medicine, University of Missouri-Columbia School of Medicine, Columbia, Missouri, United States
3 Child Health, University of Missouri, Columbia, Missouri, United States
4 Deptartment of Internal Medicine, University of Arizona, Tucson, Arizona, United States
5 Hypertension and Vascular Disease Unit, Wake Forest University, Winstom-Salem, North Carolina, United States
* To whom correspondence should be addressed. E-mail: sowersj{at}health.missouri.edu.
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 TG(mRen2)27 rat (Ren2). The Ren2 over expresses the mouse renin transgene with resultant hypertension, insulin resistance, and cardiovascular damage. Young (6-7 week 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 three weeks. 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 to SD littermates. Renin inhibition and blockade of the AT1R both 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.
