ANG II type 1A receptor signaling causes unfavorable scar dynamics in the postinfarct heart.

Blockade of ANG II type IA receptor (AT_1A) is known to attenuate postinfarction [postmyocardial infarction (post-MI)] heart failure, accompanying reduction in fibrosis of the noninfarcted area. In the present study, we investigated the influence of AT_1A blockade on the infarcted tissue itself. Consistent with earlier reports, AT_1A knockout (AT_1AKO) mice showed significantly attenuated left ventricular (LV) remodeling (dilatation) and dysfunction compared with wild-type (WT) mice. Morphometry revealed that the infarcted wall was thicker and had a smaller circumferential length in AT_1AKO than WT hearts. In addition, significantly greater numbers of cells were present within infarcts in ATIAKO hearts 4 wk post-MI; most notably, there was an abundance of vessels and myofibroblasts. One week post-MI, the incidence of apoptosis among granulation tissue cells was fewer (3.3 ± 0.4 vs. 4.4 ± 0.5% in WT, P < 0.05), whereas vessel proliferation was higher in AT_1AKO hearts, which likely explains the later abundance of cells within the scar tissue. Insulin-like growth factor receptor-I was upregulated and its downstream signal protein kinase B (Akt) was significantly activated in infarcted AT_1AKO hearts compared with WT hearts. Inactivation of Akt with wortmannin partially but significantly prevented the benefits observed in AT_1AKO. Collectively, in AT_1AKO hearts, Akt-mediated granulation tissue cell proliferation and preservation resulting from antiapoptosis likely contributed to an abundant cell population that altered the infarct scar structure, thereby reducing wall stress and attenuating LV dilatation and dysfunction at the chronic stage. In conclusion, altered structural dynamics of infarct scar and increasing myocardial fibrosis may be responsible for the deleterious effects of AT_1A signaling following MI. [ABSTRACT FROM AUTHOR]