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

作者：Li Yiwen; Takemura Genzou; Okada Hideshi; Miyata Shusaku; Kanamori Hiromitsu; Maruyama Rumi; Esaki Masayasu; Li Longhu; Ogino Atsushi; Ohno Takamasa; Kondo Takehito; Nakagawa Munehiro; Minatoguchi Shinya; Fujiwara Takako; Fujiwara Hisayoshi^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2007, 292(2): H946-H953.

DOI：10.1152/ajpheart.00361.2006

• angiotensin II
• apoptosis
• granulation tissue
• heart failure
• myocardial infarction
• myofibroblast
• scar

Blockade of ANG II type 1A 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(1A)KO) 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(1A)KO than WT hearts. In addition, significantly greater numbers of cells were present within infarcts in AT(1A)KO 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(1A)KO 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(1A)KO hearts compared with WT hearts. Inactivation of Akt with wortmannin partially but significantly prevented the benefits observed in AT(1A)KO. Collectively, in AT(1A)KO 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.

• 出版日期2007-2
• 单位浙江大学