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Diabetes 51:2709-2718, 2002
© 2002 by the American Diabetes Association, Inc.
Expression of Connective Tissue Growth Factor Is Increased in Injured Myocardium Associated With Protein Kinase C ß2 Activation and Diabetes
1 Research Division, Joslin Diabetes Center, Boston, Massachusetts
2 Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
3 Cardiovascular Research, Lilly Research Laboratories, Indianapolis, Indiana
Protein kinase C (PKC) ß isoform activity is increased in myocardium of diabetic rodents and heart failure patients. Transgenic mice overexpressing PKCß2 (PKCß2Tg) in the myocardium exhibit cardiomyopathy and cardiac fibrosis. In this study, we characterized the expression of connective tissue growth factor (CTGF) and transforming growth factor ß (TGFß) with the development of fibrosis in heart from PKCß2Tg mice at 4–16 weeks of age. Heart-to-body weight ratios of transgenic mice increased at 8 and 12 weeks, indicating hypertrophy, and ratios did not differ at 16 weeks. Collagen VI and fibronectin mRNA expression increased in PKCß2Tg hearts at 4–12 weeks. Histological examination revealed myocyte hypertrophy and fibrosis in 4- to 16-week PKCß2Tg hearts. CTGF expression increased in PKCß2Tg hearts at all ages, whereas TGFß increased only at 8 and 12 weeks. In 8-week diabetic mouse heart, CTGF and TGFß expression increased two- and fourfold, respectively. Similarly, CTGF expression increased in rat hearts at 2–8 weeks of diabetes. This is the first report of increased CTGF expression in myocardium of diabetic rodents suggesting that cardiac injury associated with PKCß2 activation, diabetes, or heart failure is marked by increased CTGF expression. CTGF could act independently or together with other cytokines to induce cardiac fibrosis and dysfunction.
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