Inhibition by angiotensin II type 1 receptor antagonist of cardiac phenotypic modulation after myocardial infarction

The purpose of this study was to examine the cardiac phenotype and remodeling after myocardial infarction and the effect of the angiotensin II type 1 (AT1) receptor antagonist (TCV-116) on the gene expression. Myocardial infarction in rats was produced by ligation of the coronary artery. TCV-116 (10 mg/kg/day) was administered orally to rats from 1 day after myocardial infarction. At 1, 2 and 3 weeks after myocardial infarction, blood pressure and heart rate were measured, and the heart was removed. The left ventricle was measured for infarct size and weight, and then the total RNA from the non-ischemic left ventricle was extracted. mRNAs in the non-ischemic left ventricle were measured by Northern blot analysis. The weight of the non-ischemic left ventricle was significantly increased 3 weeks after infarction. This was completely prevented by TCV 116 treatment. mRNA levels for β-myosin heavy chain (β-MHC), atrial natriuretic polypeptide (ANP), collagen types I and III and transforming growth factor-β1 (TGF-β1) in the non-ischemic left ventricle were increased by a factor of 3.0, 6.7, 7.9, 4.0 and 1.4 (P<0.01), respectively, 1 week after infarction. There was no increase in a-skeletal actin mRNA at 1 and 2 weeks, but it was increased by a factor of 2.9 (P<0.05) at 3 weeks. On the other hand, there was no change in α-MHC mRNA during the 3 weeks. TCV-116 significantly suppressed the increased gene expression of β-MHC and α-skeletal actin in the non-ischemic myocardium at all time points, and also suppressed the expression of ANP at 2 and 3 weeks. However, TCV-116 failed to inhibit the expression of collagen I and III mRNAS at 1 and 3 weeks. These results show that myocardial infarction causes a rapid shift of myocytes to fetal phenotype and a rapid activation of collagen genes in the non-ischemic myocardium. AT 1 receptor may be responsible for the phenotypic modulation of myocotes following myocardial infarction.