Zhao Zhuo, Wang Wei, Geng Jing, Wang Liqi, Su Guohai, Zhang Yun, Ge Zhiming, Kang Weiqiang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Shandong, PR China.
J Cell Biochem. 2010 Mar 1;109(4):653-62. doi: 10.1002/jcb.22441.
Angiotensin II (Ang II) plays a critical role in hypertrophy of cardiomyocytes; however, the molecular mechanism, especially the signaling cascades, in cardiomyocytes remains unclear. In the present study, we examined the mechanism of Ang II in hypertrophy of cardiomyocytes. Ang II rapidly stimulated phosphorylation of protein kinase C epsilon (PKCepsilon) in a time- and dose-dependent manner via Ang II receptor-1 (AT(1)). Furthermore, Ang II-induced extracellular signal-regulated kinase 5 (ERK5) phosphorylation and translocation was mediated through a signal pathway that involves AT(1) and PKCepsilon, which resulted in transcriptional activation of myocyte enhancer factor-2C (MEF2C) and hypertrophy. Consequently, inhibiting PKCepsilon or ERK5 by small interfering RNA (siRNA) significantly attenuated Ang II-induced MEF2C activation and hypertrophy of rat cardiomyocytes. These data provide evidence that PKCepsilon-dependent ERK5 phosphorylation and nucleocytoplasmic traffic mediates Ang II-induced MEF2C activation and cardiomyocyte hypertrophy. PKCepsilon and ERK5 may be potential targets in the treatment of pathological vascular hypertrophy associated with the enhanced renin-angiotensin system.
血管紧张素II（Ang II）在心肌细胞肥大过程中发挥关键作用；然而，心肌细胞中的分子机制，尤其是信号级联反应，仍不清楚。在本研究中，我们探究了Ang II在心肌细胞肥大中的作用机制。Ang II通过血管紧张素II受体1（AT(1)）以时间和剂量依赖的方式快速刺激蛋白激酶Cε（PKCε）的磷酸化。此外，Ang II诱导的细胞外信号调节激酶5（ERK5）的磷酸化和转位是通过一条涉及AT(1)和PKCε的信号通路介导的，这导致了心肌细胞增强因子-2C（MEF2C）的转录激活及肥大。因此，通过小干扰RNA（siRNA）抑制PKCε或ERK5可显著减弱Ang II诱导的大鼠心肌细胞MEF2C激活和肥大。这些数据证明，PKCε依赖的ERK5磷酸化及核质转运介导了Ang II诱导的MEF2C激活和心肌细胞肥大。PKCε和ERK5可能是治疗与肾素-血管紧张素系统增强相关的病理性血管肥大的潜在靶点。
