Geng Jing, Zhao Zhuo, Kang Weiqiang, Wang Wei, Liu Guanghui, Sun Yingying, Zhang Yun, Ge Zhiming
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012, PR China.
Biochem Biophys Res Commun. 2009 Oct 23;388(3):517-22. doi: 10.1016/j.bbrc.2009.08.025. Epub 2009 Aug 8.
Angiotensin II plays a critical role in hypertrophy of vascular smooth muscle cells, however, the molecular underpinnings remain unclear. The present study indicated that AT1/PKC/PKD pathway was able to regulate downstream ERK5, affecting pro-hypertrophic responses to Ang II. Ang II-stimulated phosphorylation of ERK5 in a time- and dose-dependent manner in human aortic smooth muscle cells (HASMCs). The pharmacological inhibitors for AT1 and PKCs significantly inhibited Ang II-induced ERK5 activation, suggesting the involvement of the AT1/PKC pathway. In particular, PKD was critical for Ang II-induced ERK5 activation since silencing PKD by siRNA markedly inhibited Ang II-induced ERK5 activation. Consequently, we found that Losartan, Gö 6983 and PKD siRNA significantly attenuated ERK5 activated translocation and hypertrophy of HASMCs by Ang II. Taken together, we demonstrated for the first time that Ang II activates ERK5 via the AT1/PKC/PKD pathway and revealed a critical role of ERK5 in Ang II-induced HASMCs hypertrophy.
血管紧张素II在血管平滑肌细胞肥大中起关键作用，然而，其分子机制仍不清楚。本研究表明，AT1/PKC/PKD途径能够调节下游的ERK5，影响对血管紧张素II的促肥大反应。血管紧张素II在人主动脉平滑肌细胞（HASMCs）中以时间和剂量依赖的方式刺激ERK5磷酸化。AT1和PKC的药理学抑制剂显著抑制血管紧张素II诱导的ERK5激活，提示AT1/PKC途径参与其中。特别地，PKD对血管紧张素II诱导的ERK5激活至关重要，因为通过siRNA沉默PKD可显著抑制血管紧张素II诱导的ERK5激活。因此，我们发现氯沙坦、Gö 6983和PKD siRNA可显著减弱血管紧张素II诱导的HASMCs中ERK5的激活转位和肥大。综上所述，我们首次证明血管紧张素II通过AT1/PKC/PKD途径激活ERK5，并揭示了ERK5在血管紧张素II诱导的HASMCs肥大中的关键作用。
