Roles of Insulin-like growth factor-II receptor signaling pathway in cardiomyocytes apoptosis induced by Angiotensin II

• Main Authors: Chun-Hsien Chu, 朱俊憲
• Other Authors: Chih-Yang Huang, Ph. D.
• Format: Others
• Language: zh-TW
• Published: 2003
• Online Access: http://ndltd.ncl.edu.tw/handle/3fe7yc

碩士 === 中山醫學大學 === 生物化學研究所 === 91 === Abstract Excessive apoptosis of cardiomyocytes was suggested to be a possible mechanism in the pathogenesis of heart disease, such as dilated cardiomyopathy and heart failure. Angiotensin II (AngII), which induce apoptosis of adult ventricular myocytes in vitro, may get involved not only in the etiology of hypertension but also in the pathophysiololgy of cardiovascular disease in human. Furthermore, it is known that IGF-I and IGF-II play important roles in the development of fetal cardiomyocytes. Insulin-like growth factor-I (IGF-I) is a autocrine mediator of growth response of Ang-II in skeletal muscle cell in vitro, but whether AngII also stimulates gene expression of cardiac insulin-like growth factor II in cardiomyocytes, and how this growth factor exerts its effect are unknown. In the present study, it was reconfirmed that the inactivation of IGF-I receptor by antibodies is necessary for IGF-II to induce apoptosis of cardiomyocytes through the activation of calcineurin by IGF-II receptor. Moreover, it was also identified that AngII-induced apoptosis may be mediated by IGF-II and AngII may regulated the activity of IGFIIR-mediated signaling pathways. The results showed that in the in vitro system, AngII can activate ERK and JNK to induce the gene expressions of IGF-II and IGF-II receptor, both of which further stimulate cardiomyctres apoptosis by Ca++ influx and activating the calcineurin pathways. Similarly, in the AngII-inducing model of the 1 to 20-day abdominal aorta coarctation in SD rats, increasing levels of IGF-II as well as its receptor and the pro-apoptotic protein caspase9 in left ventricular were also found. This is the first demonstration that ERK and JNK mediated the AngII-induced expressions of IGF-II and IGF-II receptor which further activate calcineurin signaling, contributing to cardiomyoctye apoptosis.