Molecular pharmacological analysis of role of angiotension II in cardio vascular damage

细胞表型调节及各种生长因子和细胞外基质基因表达的增强在病理性心肌肥大和血管增厚的发展中起重要作用。病理性心肌肥大不仅伴随着心肌细胞肥大，还伴随着心肌细胞向胎儿表型和间质纤维化的转变，这有助于心脏功能的调节和心力衰竭的发生。在这项研究中，我们研究了血管紧张素II在心血管疾病中的作用。在高血压大鼠中，AT1受体拮抗剂可显著缓解心脏肥厚。此外，AT1受体拮抗剂可以阻止心肌细胞从成人表型向胎儿表型的转变，并抑制纤维化相关基因如胶原蛋白和tgf - β 1的表达。AT1受体拮抗剂对心肌肥厚和基因表达的影响比钙通道拮抗剂更强。因此，局部肾素-血管紧张素系统负责病理性心脏肥大和重构。球囊损伤显著增加原癌基因、生长因子和细胞外基质成分的表达。AT1受体拮抗剂可以防止大鼠球囊损伤动脉内膜增厚，从而支持AT1受体在血管增厚中的关键作用。AT1受体拮抗剂的这种抗增殖作用与抑制损伤动脉中c-fos、c-jun、Egr-1和纤维连接蛋白的表达增加有关。因此，体内AT1受体拮抗剂可以有效抑制生长相关基因和细胞外基质基因的表达或细胞表型调节。AT1受体拮抗剂的这些细胞和分子作用可能部分有助于心血管疾病的有益作用。

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.