Yamazaki T, Shiojima I, Komuro I, Nagai R, Yazaki Y
Department of Medicine III, Tokyo University School of Medicine, Japan.
J Hypertens Suppl. 1994 Dec;12(10):S153-7.
To elucidate the regulation of cardiac gene expression by mechanical stress and to analyse molecular mechanisms associated with the involvement of angiotensin II (Ang II) in the development of cardiac hypertrophy and dysfunction.
Neonatal rat cardiocytes were cultured in deformable silicone dishes, and mechanical stress was imposed on the cardiocytes by stretching them. In in vivo studies, spontaneously hypertensive rats (SHR) were treated with a non-peptide, specific Ang II type 1 receptor antagonist, TCV 116.
Expression of c-fos was rapidly induced, and fetal type genes such as skeletal alpha actin and beta myosin heavy chain genes were re-expressed by stretching. The mechanical stress decreased the expression of Ca(2+)-ATPase in the sarcoplasmic reticulum. With regard to signals for the development of cardiac hypertrophy, mechanical stress evoked c-fos expression via the activation of protein kinase C. The phosphorylation cascade (sequential activation of protein kinase C, Raf-1 kinase, mitogen-activated protein kinase kinase, mitogen-activated protein kinase and S6 kinase), which may be involved in protein synthesis and gene expression, was activated by mechanical stress in cardiocytes. Stretch-induced cardiac cellular hypertrophy was partially inhibited by TCV 116. TCV 116 treatment of SHR reduced left ventricular weight, left ventricular wall thickness, myocyte transverse diameter, V3 myosin heavy chain levels and the interstitial collagen volume fraction.
These results indicate that Ang II may, in part, mediate the stretch-induced hypertrophic growth of cardiomyocytes via the type 1 Ang II receptor.
阐明机械应力对心脏基因表达的调控，并分析与血管紧张素II（Ang II）参与心脏肥大和功能障碍发生相关的分子机制。
将新生大鼠心肌细胞培养在可变形的硅胶培养皿中，通过拉伸对心肌细胞施加机械应力。在体内研究中，用非肽类特异性Ang II 1型受体拮抗剂TCV 116治疗自发性高血压大鼠（SHR）。
拉伸可迅速诱导c-fos表达，并使胎儿型基因如骨骼肌α-肌动蛋白和β-肌球蛋白重链基因重新表达。机械应力降低了肌浆网中Ca(2+)-ATPase的表达。关于心脏肥大发生的信号，机械应力通过激活蛋白激酶C诱发c-fos表达。可能参与蛋白质合成和基因表达的磷酸化级联反应（蛋白激酶C、Raf-1激酶、丝裂原活化蛋白激酶激酶、丝裂原活化蛋白激酶和S6激酶的顺序激活）在心肌细胞中被机械应力激活。TCV 116部分抑制了拉伸诱导的心脏细胞肥大。用TCV 116治疗SHR可降低左心室重量、左心室壁厚度、心肌细胞横径、V3肌球蛋白重链水平和间质胶原体积分数。
这些结果表明，Ang II可能部分通过Ang II 1型受体介导拉伸诱导的心肌细胞肥大生长。
