Dataset Information
Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells.
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ABSTRACT: Background and purpose
Transmembrane 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 approach
Cell viability assay, flow cytometry, Western blot, mitochondrial membrane potential assay, immunogold labelling and co-immunoprecipitation (co-IP) were performed.Key results
Hydrogen peroxide (H2 O2 ) 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 cytochrome c from 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 H2 O2 but 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 implications
These results suggest that TMEM16A participates in H2 O2 -induced apoptosis via modulation of mitochondrial membrane permeability in VSMCs. This study establishes TMEM16A as a target for therapy of several remodelling-related diseases.
SUBMITTER: Zeng JW
PROVIDER: S-EPMC6109215 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells.
British journal of pharmacology 20180809 18
<h4>Background and purpose</h4>Transmembrane member 16A (TMEM16A), an intrinsic constituent of the Ca<sup>2+</sup> -activated Cl<sup>-</sup> 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.<h4>Experimental approach ...[more]
