Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Mizuno T, Takano H, Hiroi Y, Ueki K, Tobe K
Third Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan.
Circ Res. 1995 Aug;77(2):258-65. doi: 10.1161/01.res.77.2.258.
We have previously shown that mechanical stress induces activation of protein kinases and increases in specific gene expression and protein synthesis in cardiac myocytes, all of which are similar to those evoked by humoral factors such as growth factors and hormones. Many lines of evidence have suggested that angiotensin II (Ang II) plays a vital role in cardiac hypertrophy, and it has been reported that secretion of Ang II from cultured cardiac myocytes was induced by mechanical stretch. To examine the role of Ang II in mechanical stress-induced cardiac hypertrophy, we stretched neonatal rat cardiac myocytes in the absence or presence of the Ang II receptor antagonists saralasin (an antagonist of both type 1 and type 2 receptors), CV-11974 (a type 1 receptor-specific antagonist), and PD123319 (a type 2 receptor-specific antagonist). Stretching cardiac myocytes by 20% using deformable silicone dishes rapidly increased the activities of mitogen-activated protein (MAP) kinase kinase activators and MAP kinases. Both saralasin and CV-11974 partially inhibited the stretch-induced increases in the activities of both kinases, whereas PD123319 showed no inhibitory effects. Stretching cardiac myocytes increased amino acid incorporation, which was also inhibited by approximately 70% with the pretreatment by saralasin or CV-11974. When the culture medium conditioned by stretching cardiocytes was transferred to nonstretched cardiac myocytes, the increase in MAP kinase activity was observed, and this increase was completely suppressed by saralasin or CV-11974. These results suggest that Ang II plays an important role in mechanical stress-induced cardiac hypertrophy and that there are also other (possibly nonsecretory) factors to induce hypertrophic responses.
我们之前已经表明，机械应力可诱导蛋白激酶的激活，并增加心肌细胞中特定基因的表达和蛋白质合成，所有这些都与生长因子和激素等体液因子所引发的情况相似。许多证据表明，血管紧张素II（Ang II）在心肌肥大中起着至关重要的作用，并且据报道，机械拉伸可诱导培养的心肌细胞分泌Ang II。为了研究Ang II在机械应力诱导的心肌肥大中的作用，我们在不存在或存在Ang II受体拮抗剂沙拉新（1型和2型受体的拮抗剂）、CV-11974（1型受体特异性拮抗剂）和PD123319（2型受体特异性拮抗剂）的情况下拉伸新生大鼠心肌细胞。使用可变形硅胶培养皿将心肌细胞拉伸20%可迅速增加丝裂原活化蛋白（MAP）激酶激酶激活剂和MAP激酶的活性。沙拉新和CV-11974均部分抑制了拉伸诱导的两种激酶活性的增加，而PD123319则未显示出抑制作用。拉伸心肌细胞增加了氨基酸掺入，用沙拉新或CV-11974预处理也可使其受到约70%的抑制。当将拉伸心肌细胞条件培养基转移至未拉伸的心肌细胞时，观察到MAP激酶活性增加，并且这种增加被沙拉新或CV-11974完全抑制。这些结果表明，Ang II在机械应力诱导的心肌肥大中起重要作用，并且还存在其他（可能是非分泌性的）因子来诱导肥大反应。
