Expression of Connective Tissue Growth Factor Is Increased in Injured Myocardium Associated With Protein Kinase C β2 Activation and Diabetes
- Kerrie J. Way1,
- Keiji Isshiki1,
- Kiyoshi Suzuma1,
- Tamotsu Yokota1,
- Dmitriy Zvagelsky2,
- Frederick J. Schoen2,
- George E. Sandusky3,
- Penelope A. Pechous3,
- Chris J. Vlahos3,
- Hisao Wakasaki1 and
- George L. King1
- 1Research Division, Joslin Diabetes Center, Boston, Massachusetts
- 2Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
- 3Cardiovascular Research, Lilly Research Laboratories, Indianapolis, Indiana
Abstract
Protein kinase C (PKC) β isoform activity is increased in myocardium of diabetic rodents and heart failure patients. Transgenic mice overexpressing PKCβ2 (PKCβ2Tg) 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 β (TGFβ) with the development of fibrosis in heart from PKCβ2Tg 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 PKCβ2Tg hearts at 4–12 weeks. Histological examination revealed myocyte hypertrophy and fibrosis in 4- to 16-week PKCβ2Tg hearts. CTGF expression increased in PKCβ2Tg hearts at all ages, whereas TGFβ increased only at 8 and 12 weeks. In 8-week diabetic mouse heart, CTGF and TGFβ 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 PKCβ2 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.
Footnotes
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Address correspondence and reprint requests to George L. King, MD, Harvard Medical School, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: george.king{at}joslin.harvard.edu.
Received for publication 26 October 2001 and accepted in revised form 10 June 2002.
CTGF, connective tissue growth factor; ECM, extracellular matrix; DAG, diacylglycerol; PKC, protein kinase C; STZ, streptozotocin; TBP, TATA binding protein; TGFβ, transforming growth factor β.
- DIABETES
