Mechanisms of cardiac hypertrophy and injury--possible role of protein kinase C activation.
To examine the molecular mechanisms by which mechanical stimuli induced cardiac hypertrophy and injury, we cultured rat neonatal cardiocytes in deformable dishes and imposed an in vitro mechanical load by stretching the adherent cells. Myocyte stretching increased total cell RNA content and mRNA levels of c-fos. Marked accumulation of c-fos mRNA followed increases in intracellular Na+ and protein kinase C activation. The accumulation of c-fos mRNA by cardiocyte stretching was suppressed by protein kinase C inhibitors but not by stretch channel blockers. Moreover, myocyte stretching increased inositol phosphate levels, and activation of protein kinase C by phorbolesters stumulated the expression of c-fos. We also examined TGF beta expression in the heart. TGF beta is known to be stimulated by protein kinase C activation, and the mRNA level of TGF beta was increased in in vivo heart by pressure overload. Furthermore, collagen synthesis was stimulated by TGF beta in cultured fibroblasts from hearts. These findings suggest that hemodynamic overload may stimulate cardiac hypertrophy and induce cardiac injury (fibrosis) through protein kinase C activation.
Komuro
I
I
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Katoh
Y
Y
Hoh
E
E
Takaku
F
F
Yazaki
Y
Y
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D003094:Collagen / Q000096:biosynthesis; D004719:Endomyocardial Fibrosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004789:Enzyme Activation; D015870:Gene Expression; D016762:Genes, fos; D006439:Hemodynamics; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D012313:RNA; D003094:Collagen; D011493:Protein Kinase C