Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells
Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells
复制标题
跨膜成员16A通过促进血管平滑肌细胞中线粒体依赖性途径参与过氧化氢诱导的细胞凋亡
DOI：
10.1111/bph.14432
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Guan Yong Yuan
中科院分区：
文献类型：
--
作者：
Zeng Jia Wei;Chen Bao Yi;Lv Xiao Fei;Sun Lu;Zeng Xue Lin;Zheng Hua Qing;Du Yan Hua;Wang Guan Lei;Ma Ming Ming;Guan Yong Yuan
Background and PurposeTransmembrane member 16A (TMEM16A), an intrinsic constituent of the Ca2+‐activated Cl−channel, is involved in vascular smooth muscle cell (VSMC) proliferation and hypertension‐induced cerebrovascular remodelling. However, the functional significance of TMEM16A for apoptosis in basilar artery smooth muscle cells (BASMCs) remains elusive. Here, we investigated whether and how TMEM16A contributes to apoptosis in BASMCs.Experimental ApproachCell viability assay, flow cytometry, Western blot, mitochondrial membrane potential assay, immunogold labelling and co‐immunoprecipitation (co‐IP) were performed.Key ResultsHydrogen peroxide (H2O2) induced BASMC apoptosis through a mitochondria‐dependent pathway, including by increasing the apoptosis rate, down‐regulating the ratio of Bcl‐2/Bax and potentiating the loss of the mitochondrial membrane potential and release of cytochromecfrom the mitochondria to the cytoplasm. These effects were all reversed by the silencing of TMEM16A and were further potentiated by the overexpression of TMEM16A. Endogenous TMEM16A was detected in the mitochondrial fraction. Co‐IP revealed an interaction between TMEM16A and cyclophilin D, a component of the mitochondrial permeability transition pore (mPTP). This interaction was up‐regulated by H2O2but restricted by cyclosporin A, an inhibitor of cyclophilin D. TMEM16A increased mPTP opening, resulting in the activation of caspase‐9 and caspase‐3. The results obtained with cultured BASMCs from TMEM16A smooth muscle‐specific knock‐in mice were consistent with those from rat BASMCs.Conclusions and ImplicationsThese results suggest that TMEM16A participates in H2O2‐induced apoptosisviamodulation of mitochondrial membrane permeability in VSMCs. This study establishes TMEM16A as a target for therapy of several remodelling‐related diseases.
