Expression of connective tissue growth factor is increased in injured myocardium associated with protein kinase C beta2 activation and diabetes.
Protein kinase C (PKC) beta isoform activity is increased in myocardium of diabetic rodents and heart failure patients. Transgenic mice overexpressing PKCbeta2 (PKCbeta2Tg) 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 beta (TGFbeta) with the development of fibrosis in heart from PKCbeta2Tg 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 PKCbeta2Tg hearts at 4-12 weeks. Histological examination revealed myocyte hypertrophy and fibrosis in 4- to 16-week PKCbeta2Tg hearts. CTGF expression increased in PKCbeta2Tg hearts at all ages, whereas TGFbeta increased only at 8 and 12 weeks. In 8-week diabetic mouse heart, CTGF and TGFbeta 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 PKCbeta2 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.
Way
Kerrie J
KJ
Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Isshiki
Keiji
K
Suzuma
Kiyoshi
K
Yokota
Tamotsu
T
Zvagelsky
Dmitriy
D
Schoen
Frederick J
FJ
Sandusky
George E
GE
Pechous
Penelope A
PA
Vlahos
Chris J
CJ
Wakasaki
Hisao
H
King
George L
GL
D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D006133:Growth Substances / Q000378:metabolism*; D006352:Heart Ventricles; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007158:Immunologic Techniques; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D051381:Rats; D013194:Staining and Labeling; D016212:Transforming Growth Factor beta / Q000378:metabolism
C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D011493:Protein Kinase C; D064546:Protein Kinase C beta