Nitric oxide mediates benefits of angiotensin II type 2 receptor overexpression during post-infarct remodeling

We hypothesized that nitric oxide (NO) mediates the benefits of cardiac angiotensin II type 2 (AT(2)-R) overexpression during postmyocardial infarction (post-MI) remodeling. Eleven wild-type (WT) C57BL/6 mice and 28 transgenic (TG) mice with AT(2)-R overexpression were studied by cardiac magnetic resonance imaging (CMR) at baseline and days 1 and 28 post-MI induced by left anterior descending artery occlusion and reperfusion. Sixteen TG mice were treated from day 1 through 28 post-MI with the NO synthase inhibitor N-G-nitro-L-arginine methyl ester in drinking water at 1 mg/mL (TG-Rx). Left ventricular mass index (LVMI), end-diastolic volume index (EDVI) and end-systolic volume index (ESVI), wall thickness, percent thickening, and ejection fraction (EF) were measured. Infarct size on day 1 was assessed by post-contrast CMR. Interstitial collagen was quantified in noninfarcted regions. At baseline, heart rate (HR), blood pressure ( BP), LVMI, EDVI, and ESVI were similar between groups, as were infarct size and weekly post-MI HR and systolic BP. By day 28 post-MI, EDVI and ESVI were similar in WT and TG-Rx, but significantly lower in TG (ESVI: 1.41 +/- 0.18 muL/g versus 2.53 +/- 0.14 muL/g in WT; 2.17 +/- 0.14 muL/g in TG-Rx; P < 0.008 for both). At day 28, EF was higher in TG (46.3% +/- 2.9%) compared with WT and TG-Rx (32.7 +/- 2.3% and 33.7 +/- 2.3, respectively; P < 0.003 for both). Wall thickening at day 28 post-MI was greater in the base and mid-LV in TG than WT and TG-Rx. Noninfarcted region interstitial collagen was similar between groups. Thus, the NO pathway may mediate much of the benefits of cardiac AT(2)-R overexpression during post-MI remodeling.