| Budget Amount *help |
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1996: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1995: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
Cellular phenotypic modulation and the enhanced gene expression of various growth factors and extracellular matrix play an important role in the development of pathologic cardiac hypertrophy and vascular thickening. Pathologic cardiac hypertrophy is accompanied not only by myocyte hypertrophy but also by the shift of myocytes to a fetal phenotype and interstitial fibrosis, which contribute to the modulation of cardiac performance and the onset of heart failure. In this study, we examined the role of angiotensin II in cardiovascular diseases. In hypertensive rats, AT1 receptor antagonist significantly regresses cardiac hypertrophy. Furthermore, AT1 receptor antagonist prevents the shift of cardiac myocytes from an adult to a fetal phenotype, and suppresses the expression of fibrosis-related genes such as collagen and TGF-beta1. These effects of AT1 receptor antagonist on cardiac hypertrophy and gene expressions are more potent than those of calcium channel antagonist. Thus, local renin-angiotensin system is responsible for pathologic cardiac hypertrophy and remodeling. Balloon injury dramatically increases the expression of proto-oncogenes, growth factors and extracellular matrix components. AT1 receptor antagonist can prevent neointimal thickening in balloon-injured artery of rats, thereby supporting the critical role of AT1 receptor in vascular thickening. This anti-proliferative effect of AT1 receptor antagonist is associated with the inhibition of the increased expression of c-fos, c-jun, Egr-1 and fibronectin in injured artery. Thus, AT1 receptor antagonist in vivo potently inhibits either the growth-related gene and extracellular matrix gene expressions or the celluar phenotypic modulation. These cellular and molecular effects of AT1 receptor antagonist may partially contribute to the beneficial effects on cardiovascular diseases.
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