Abstract
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 dnPKCalpha, -epsilon, and -zeta isoforms suppressed AngII-induced CTGF expression in cardiomyocytes. In contrast, expression of dominant negative PKCdelta significantly increased AngII-induced CTGF expression, whereas expression of wild type PKCdelta inhibited this induction. This inhibitory effect was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of PKCdelta (deltaTg 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.
Highlights
Myocardial pathologies in diabetic patients include diastolic dysfunction, microvascular disease, and interstitial fibrosis, which could be the result of active tissue remodeling that can contribute to the reduced cardiac contractility [1]
Effect of Protein kinase C (PKC) Activation on angiotensin II (AngII)-induced connective tissue growth factor (CTGF) Expression in Cardiomyocytes—Because we have previously reported that targeted overexpression of PKC2 in the myocardium induced CTGF expression and severe fibrosis [4, 29], we examined the effects of PKC and its isoforms activation on CTGF expression in this study
CTGF mRNA expression has been previously reported to be increased in the myocardium of cardiac PKC2 transgenic mice [4], expression of dnPKC2 did not reduce CTGF expression induced by AngII as compared with Ad-GFP-infected control cells stimulated with AngII
Summary
Myocardial pathologies in diabetic patients include diastolic dysfunction, microvascular disease, and interstitial fibrosis, which could be the result of active tissue remodeling that can contribute to the reduced cardiac contractility [1]. Incubation of cultured cardiomyocytes with AngII increased CTGF mRNA expression by 2-fold, which was blocked by candesartan and a general PKC inhibitor, GF109203X.
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