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 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.
He
Zhiheng
Z
Research Division, Joslin Diabetes Center, Harvard Medical School and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
Way
Kerrie J
KJ
Arikawa
Emi
E
Chou
Eva
E
Opland
Darren M
DM
Clermont
Allen
A
Isshiki
Keiji
K
Ma
Ronald C W
RC
Scott
Joshua A
JA
Schoen
Frederick J
FJ
Feener
Edward P
EP
King
George L
GL
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D003920:Diabetes Mellitus; D005786:Gene Expression Regulation / Q000502:physiology; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats
C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D011493:Protein Kinase C