Class II phosphatidylinositol 3-kinase α and β isoforms are required for vascular smooth muscle Rho activation, contraction and blood pressure regulation in mice
Class II phosphatidylinositol 3-kinase α and β isoforms are required for vascular smooth muscle Rho activation, contraction and blood pressure regulation in mice
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DOI：
10.1186/s12576-020-00745-2
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发表时间：
2020-03-19
影响因子：
2.3
通讯作者：
Takuwa, Yoh
中科院分区：
文献类型：
--
作者：
Islam, Shahidul;Yoshioka, Kazuaki;Takuwa, Yoh
II类磷脂酰肌醇3-激酶（PI 3 K）、PI 3 K-C2 α和PI 3 K-C2 β参与细胞过程，包括内吞作用、纤毛形成和自噬。然而，PI 3 K-C2 α和PI 3 K-C2 β在生物体水平上的作用还没有得到很好的理解。我们发现，具有PI 3 K-C2 α的平滑肌特异性KO和整体PI 3 K-C2 β KO的双敲除（KO）小鼠，但没有PI 3 K-C2 α或PI 3 K-C2 β的单KO小鼠，表现出动脉血压降低和分离主动脉环收缩反应的显著减弱。在野生型血管平滑肌细胞中，PI 3 K-C2 α和PI 3 K-C2 β的双敲低而非任一PI 3 K的单敲低显著抑制收缩，降低20-kDa肌球蛋白轻链的磷酸化和MYPT 1和Rho活化，但不抑制细胞内Ca 2+动员。这些数据表明，PI 3 K-C2 α和PI 3 K-C2 β主要通过参与Rho激活而对血管平滑肌收缩和血压调节发挥冗余但重要的作用。
Class II phosphatidylinositol 3-kinases (PI3K), PI3K-C2 alpha and PI3K-C2 beta, are involved in cellular processes including endocytosis, cilia formation and autophagy. However, the role of PI3K-C2 alpha and PI3K-C2 beta at the organismal level is not well understood. We found that double knockout (KO) mice with both smooth muscle-specific KO of PI3K-C2 alpha and global PI3K-C2 beta KO, but not single KO mice of either PI3K-C2 alpha or PI3K-C2 beta, exhibited reductions in arterial blood pressure and substantial attenuation of contractile responses of isolated aortic rings. In wild-type vascular smooth muscle cells, double knockdown of PI3K-C2 alpha and PI3K-C2 beta but not single knockdown of either PI3K markedly inhibited contraction with reduced phosphorylation of 20-kDa myosin light chain and MYPT1 and Rho activation, but without inhibition of the intracellular Ca2+ mobilization. These data indicate that PI3K-C2 alpha and PI3K-C2 beta play the redundant but essential role for vascular smooth muscle contraction and blood pressure regulation mainly through their involvement in Rho activation.