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

Adam Whaley-Connell, Javad Habibi, Shawna A. Cooper, Vincent G. DeMarco, Melvin R. Hayden, Craig S. Stump, Daniel Link, Carlos M. Ferrario, James R. Sowers

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Angiotensin II (Ang II) stimulation of the Ang type 1 receptor (AT 1R) 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.

Original languageEnglish (US)
Pages (from-to)E103-E109
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume295
Issue number1
DOIs
StatePublished - Jul 2008

Keywords

  • Cardiac remodeling
  • Oxidative stress
  • Reduced nicotinamide adenine dinucleotide phosphate oxidase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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