Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium

Protein kinase C ( PKC) and angiotensin II ( AngII) can regulate cardiac function in pathological conditions such as in diabetes or ischemic heart disease. We have reported that expression of connective tissue growth factor ( CTGF) is increased in the myocardium of diabetic mice. Now we showed that the increase in CTGF expression in cardiac tissues of streptozotocin- induced diabetic rats was reversed by captopril and islet cell transplantation. Infusion of AngII in rats increased CTGF mRNA expression by 15- fold, which was completely inhibited by co- infusion with AT1 receptor antagonist, candesartan. Similarly, incubation of cultured cardiomyocytes with AngII increased CTGF mRNA expression by 2- fold, which was blocked by candesartan and a general PKC inhibitor, GF109203X. The role of PKC isoform- dependent action was further studied using adenoviral vector- mediated gene transfer of dominant negative ( dn) PKC or wild type PKC isoforms. Expression of dnPKC alpha, -epsilon, and - zeta isoforms suppressed AngII- induced CTGF expression in cardiomyocytes. In contrast, expression of dominant negative PKC delta significantly increased AngII- induced CTGF expression, whereas expression of wild type PKC delta inhibited this induction. This inhibitory effect was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of PKC delta ( delta Tg mice). Thus, AngII can regulate CTGF expression in cardiomyocytes through a PKC activation- mediated pathway in an isoform-selective manner both in physiological and diabetic states and may contribute to the development of cardiac fibrosis in diabetic cardiomyopathy.