Abstract 639: Angiotensin 1-7 Contributes To Cardioprotective Effects Of Cardiac Overexpression Of Angiotensin II Type 2 Receptor In Mice Post-MI
Angiotensin II (Ang II) acting on AT1 receptor plays a pivotal role in the pathophysiology of cardiovascular disease, whereas AT2 has been considered cardioprotective, although the mechanisms are not fully understood. Recently studies suggest AT2 interacts with ACE2, an enzyme known to release Ang 1-7 from Ang II. Thus we hypothesize that Ang 1-7 contributes to cardioprotective effects of AT2, possibly via AT2/ACE2/Ang 1-7 cascade. Transgenic mice with AT2 specifically overexpressed in the heart (Tg-AT2) and their wild-type littermates (WT) were subjected to myocardial infarction (MI) or sham MI and divided into 1) sham MI; 2) MI + vehicle; and 3) MI + Mas receptor antagonist ([D-Ala7-Ang 1-7], A779, 0.5 mg/kg/day via osmotic mini pump). Treatments were started on the same day of MI and continued for 8 weeks. Our data show that AT2 and ACE2 protein expression in the heart was significantly increased in Tg-AT2 mice, whereas AT1 protein remained unchanged. Systolic blood pressure (SBP) and cardiac phenotypes did not differ between strains under basal conditions. MI increased myocyte cross-sectional area (MCSA), interstitial collagen fraction (ICF), left ventricular diastolic dimension (LVDd) and capillary density, and decreased LV ejection fraction (EF) in both strains; however, these pathological responses were diminished in Tg-AT2. Blockade of Mas receptor with A779 attenuated the cardioprotective effects observed in Tg-AT2 mice (Table). Infarct size (IS) did not differ among groups. Our findings suggest that overexpression/activation of AT2 protects against cardiac remodeling and dysfunction post MI, which is mediated in part through Ang 1-7 acting on the Mas receptor.
Author Disclosures: J. Xu: None. O.A. Carretero: None. L. Zhu: None. P. Harding: None. N. Rhaleb: None. E.G. Shesely: None. E. Peterson: None. X. Yang: None.
- © 2014 by American Heart Association, Inc.