ANG II type 1A receptor signaling causes unfavorable scar dynamics in the postinfarct heart.
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.
Li
Yiwen
Y
Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagito, Gifu 501-1194, Japan.
Takemura
Genzou
G
Okada
Hideshi
H
Miyata
Shusaku
S
Kanamori
Hiromitsu
H
Maruyama
Rumi
R
Esaki
Masayasu
M
Li
Longhu
L
Ogino
Atsushi
A
Ohno
Takamasa
T
Kondo
Takehito
T
Nakagawa
Munehiro
M
Minatoguchi
Shinya
S
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017209:Apoptosis; D001794:Blood Pressure / Q000187:drug effects; D049109:Cell Proliferation; D005355:Fibrosis; D006097:Granulation Tissue / Q000378:metabolism / Q000473:pathology; D006830:Hydralazine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D000077191:Wortmannin
D000730:Androstadienes; D000959:Antihypertensive Agents; D047428:Protein Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; D006830:Hydralazine; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin