(Circulation. 1999;100:2093-2099.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Angiotensin II Type 1A Receptor Knockout Mice Display Less Left Ventricular Remodeling and Improved Survival After Myocardial Infarction
From the Department of Cardiovascular Medicine (K.H., Y.Y., I.K.), University of Tokyo Graduate School of Medicine; Discovery Research Laboratory (T.S.), Tanabe Seiyaku Co, Ltd, Osaka; and the Institute of Applied Biochemistry (K.M.), University of Tsukuba, Ibaraki, Japan.
Correspondence to Issei Komuro, MD, PhD, Department of Cardiovascular Medicine, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.ac.jp
Background—Angiotensin II (Ang II) has been implicated in ventricular remodeling after myocardial infarction (MI), which is an important determinant for prognosis after MI. The aim of this study was to determine whether Ang II type 1A receptor (AT1A)–mediated Ang II signals are critically involved in the mortality and LV remodeling after MI.
Methods and Results—We examined survival, cardiac geometry and function, cardiac fibrosis, and gene expression of AT1A knockout (KO) mice and wild-type (WT) mice at 1 and 4 weeks after large MI. The survival rate was higher in KO mice than in WT mice at 4 weeks after MI. All WT survivors showed severe heart failure, detected by marked increases in both RV weight and lung weight. LV remodeling, such as the development of LV dilatation, LV dysfunction, and cardiac fibrosis at the noninfarcted area, were comparable in both kinds of mice at 1 week after MI. At 4 weeks after MI, however, WT mice showed more marked remodeling than KO mice. mRNA levels of AT1 at the noninfarcted area were increased from 1 to 4 weeks after MI only in WT mice, whereas levels of AT2 were not changed by MI in either kind of mouse. Accompanied by the development of geometric and structural remodeling, expression of fetal-type genes, collagen, and transforming growth factor-ß1 genes were upregulated and sustained in the noninfarcted area of WT hearts. In contrast, they were rapidly downregulated to basal levels at 4 weeks after MI in that of KO hearts.
Conclusions—These results indicate that AT1A signals play a pivotal role in the progression of LV remodeling after MI, resulting in overt heart failure.
Key Words: angiotensin • myocardial infarction • mortality • remodeling
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