SGK1 mediates the hypotonic protective effect against H2O2-induced apoptosis of rat basilar artery smooth muscle cells by inhibiting the FOXO3a/Bim signaling pathway
SGK1 mediates the hypotonic protective effect against H2O2-induced apoptosis of rat basilar artery smooth muscle cells by inhibiting the FOXO3a/Bim signaling pathway
复制标题
SGK1通过抑制FOXO3a/Bim信号通路介导对H2O2诱导的大鼠基底动脉平滑肌细胞凋亡的低渗保护作用
DOI：
10.1038/s41401-020-0357-y
复制
发表时间：
2020-03-05
影响因子：
8.2
通讯作者：
Guan, Yong-yuan
中科院分区：
文献类型：
--
作者：
Chen, Bao-yi;Huang, Cheng-cui;Guan, Yong-yuan
血清和糖皮质激素诱导型激酶-1 （SGK1）是一种受低渗刺激调节的丝氨酸/苏氨酸激酶，参与细胞周期和凋亡的调控。我们之前的研究表明，激活体积调节的Cl-通道（vrcc）可以保护大鼠基底动脉平滑肌细胞（BASMCs）免受过氧化氢（H2O2）诱导的凋亡。在本研究中，我们研究了SGK1是否参与了vrcc在basmc中的保护作用。我们发现低渗刺激显著降低h2o2诱导的细胞凋亡，增加SGK1磷酸化，但不影响SGK1蛋白表达。低压刺激对h2o2诱导的细胞凋亡的保护作用是通过抑制线粒体依赖的凋亡通路介导的，表现为Bcl-2/Bax比值升高，线粒体膜电位（MMP）稳定，细胞色素c从线粒体向细胞质释放减少，caspase-9和caspase-3的活化受到抑制。低渗刺激对h2o2诱导的细胞凋亡的保护作用分别因SGK1的下调和过表达而减弱和增强。我们进一步发现，SGK1激活显著增加叉头盒O3a （FOXO3a）磷酸化，进而抑制FOXO3a向细胞核的易位以及随后Bcl-2相互作用的细胞死亡介质（Bim）的表达。综上所述，SGK1通过抑制FOXO3a/Bim信号通路介导vrcc对h2o2诱导的BASMCs凋亡的保护作用。我们的研究结果提供了令人信服的证据，表明SGK1是vrcc和细胞凋亡之间的关键联系，并为血管细胞凋亡相关疾病（如血管重塑、血管生成和动脉粥样硬化）的治疗提供了新的思路。
Serum- and glucocorticoid-inducible kinease-1 (SGK1) is a serine/threonine kinase regulated by hypotonic stimuli, which is involved in regulation of cell cycle and apoptosis. Our previous study shows that activation of volume-regulated Cl- channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (H2O2)-induced apoptosis. In the present study, we investigated whether SGK1 was involved in the protective effect of VRCCs in BASMCs. We showed that hypotonic challenge significantly reduced H2O2-induced apoptosis, and increased SGK1 phosphorylation, but did not affect SGK1 protein expression. The protective effect of hypotonic challenge against H2O2-induced apoptosis was mediated through inhibiting mitochondria-dependent apoptotic pathway, evidenced by increased Bcl-2/Bax ratio, stabilizing mitochondrial membrane potential (MMP), decreased cytochrome c release from the mitochondria to the cytoplasm, and inhibition of the activation of caspase-9 and caspase-3. These protective effects of hypotonic challenge against H2O2-induced apoptosis was diminished and enhanced, respectively, by SGK1 knockdown and overexpression. We further revealed that SGK1 activation significantly increased forkhead box O3a (FOXO3a) phosphorylation, and then inhibited the translocation of FOXO3a into nucleus and the subsequent expression of Bcl-2 interacting mediator of cell death (Bim). In conclusion, SGK1 mediates the protective effect of VRCCs against H2O2-induced apoptosis in BASMCs via inhibiting FOXO3a/Bim signaling pathway. Our results provide compelling evidences that SGK1 is a critical link between VRCCs and apoptosis, and shed a new light on the treatment of vascular apoptosis-associated diseases, such as vascular remodeling, angiogenesis, and atherosclerosis.