Komuro I, Katoh Y, Hoh E, Takaku F, Yazaki Y
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Jpn Circ J. 1991 Nov;55(11):1149-57. doi: 10.1253/jcj.55.1149.
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.
为了研究机械刺激诱导心脏肥大和损伤的分子机制，我们将新生大鼠心肌细胞培养在可变形培养皿中，并通过拉伸贴壁细胞施加体外机械负荷。心肌细胞拉伸增加了总细胞RNA含量以及c-fos的mRNA水平。c-fos mRNA的显著积累发生在细胞内钠离子增加和蛋白激酶C激活之后。心肌细胞拉伸导致的c-fos mRNA积累被蛋白激酶C抑制剂抑制，但未被拉伸通道阻滞剂抑制。此外，心肌细胞拉伸增加了肌醇磷酸水平，佛波酯激活蛋白激酶C刺激了c-fos的表达。我们还检测了心脏中转化生长因子β（TGFβ）的表达。已知TGFβ可被蛋白激酶C激活所刺激，并且在体内心脏中，压力超负荷会使TGFβ的mRNA水平升高。此外，心脏来源的培养成纤维细胞中，TGFβ刺激了胶原蛋白合成。这些发现表明，血流动力学超负荷可能通过蛋白激酶C激活刺激心脏肥大并诱导心脏损伤（纤维化）。
