Role of angiotensin II receptor subtypes on cardiovascular remodeling induced by aortic banding

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The banding of abdominal portion of aorta induced cardiac hypertrophy accompanied with the increase in heart weight, cardiomyocyte size, coronary artery thickness and perivascular fibrosis of coronary artery. In AT2 receptor deficient (AT2KO) mice, the changes of cardiac muscle were similar to, but the changes of coronary artery were more exaggerated than in wild type (WT) mice. Valsartan, an AT 1 receptor blocker, significantly inhibited the heart weight and cardiomyocyte size both in WT and AT2KO mice. The coronary artery thickening and perivascular fibrosis were inhibited by valsartan in WT mice, but the inhibitory actions of valsartan were smaller in AT2KO mice. Apoptosis detected by TUNEL staining, single stand DNA and Hoechst33342, and Bax expression was increased in coronary artery and perivascular region. The apoptotic changes were decreased in AT2KO mice but increased by valsartan in WT mice. Fibroblasts isolated and cultured from neonatal mice skin showed an increase in collagen synthesis and TIMP-1 expression by angiotensin (Ang) II. These changes induced by Ang II were inhibited by valsartan but enhanced by AT2 antagonist, PD123319. Ang II inhibited the increase in collagen synthesis and TIMT-1 expression induced by IGF-1 in AT1KO mice. Transfection of dominant negative mutant of a tyrosine phsphatase, SHP-1, into fibroblast decreased the inhibitory actions of Ang II on collagen synthesis in AT1KO mice.These resukts suggest that AT2 receptor stimulation counter acts on the effects of AT 1 receptor stimulation to inhibit the changes of coronary artery thickening and perivascular fibrosis observed in cardiac hypertrophy.