ISSN: 1838-7640Theranostics
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Theranostics 2020; 10(9):3980-3993. doi:10.7150/thno.41028 This issue Cite
Research Paper
TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation
Department of Pharmacology and Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
*These authors contributed equally to this work.
Citation:
Lv XF, Zhang YJ, Liu X, Zheng HQ, Liu CZ, Zeng XL, Li XY, Lin XC, Lin CX, Ma MM, Zhang FR, Shang JY, Zhou JG, Liang SJ, Guan YY. TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation. Theranostics 2020; 10(9):3980-3993. doi:10.7150/thno.41028. https://www.thno.org/v10p3980.htm
Other stylesAbstract
Rationale: Transmembrane member 16A (TMEM16A) is a component of calcium-activated chloride channels that regulate vascular smooth muscle cell (SMC) proliferation and remodeling. Autophagy, a highly conserved cellular catabolic process in eukaryotes, exerts important physiological functions in vascular SMCs. In the current study, we investigated the relationship between TMEM16A and autophagy during vascular remodeling.
Methods: We generated a transgenic mouse that overexpresses TMEM16A specifically in vascular SMCs to verify the role of TMEM16A in vascular remodeling. Techniques employed included immunofluorescence, electron microscopy, co-immunoprecipitation, and Western blotting.
Results: Autophagy was activated in aortas from angiotensin II (AngII)-induced hypertensive mice with decreased TMEM16A expression. The numbers of light chain 3B (LC3B)-positive puncta in aortas correlated with the medial cross-sectional aorta areas and TMEM16A expression during hypertension. SMC-specific TMEM16A overexpression markedly inhibited AngII-induced autophagy in mouse aortas. Moreover, in mouse aortic SMCs (MASMCs), AngII-induced autophagosome formation and autophagic flux were blocked by TMEM16A upregulation and were promoted by TMEM16A knockdown. The effect of TMEM16A on autophagy was independent of the mTOR pathway, but was associated with reduced kinase activity of the vacuolar protein sorting 34 (VPS34) enzyme. Overexpression of VPS34 attenuated the effect of TMEM16A overexpression on MASMC proliferation, while the effect of TMEM16A downregulation was abrogated by a VPS34 inhibitor. Further, co-immunoprecipitation assays revealed that TMEM16A interacts with p62. TMEM16A overexpression inhibited AngII-induced p62-Bcl-2 binding and enhanced Bcl-2-Beclin-1 interactions, leading to suppression of Beclin-1/VPS34 complex formation. However, TMEM16A downregulation showed the opposite effects.
Conclusion: TMEM16A regulates the four-way interaction between p62, Bcl-2, Beclin-1, and VPS34, and coordinately prevents vascular autophagy and remodeling
Keywords: transmembrane member 16A, autophagy, vascular remodeling, vacuolar protein sorting 34, smooth muscle cell
Citation styles
APA
Lv, X.F., Zhang, Y.J., Liu, X., Zheng, H.Q., Liu, C.Z., Zeng, X.L., Li, X.Y., Lin, X.C., Lin, C.X., Ma, M.M., Zhang, F.R., Shang, J.Y., Zhou, J.G., Liang, S.J., Guan, Y.Y. (2020). TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation. Theranostics, 10(9), 3980-3993. https://doi.org/10.7150/thno.41028.
ACS
Lv, X.F.; Zhang, Y.J.; Liu, X.; Zheng, H.Q.; Liu, C.Z.; Zeng, X.L.; Li, X.Y.; Lin, X.C.; Lin, C.X.; Ma, M.M.; Zhang, F.R.; Shang, J.Y.; Zhou, J.G.; Liang, S.J.; Guan, Y.Y. TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation. Theranostics 2020, 10 (9), 3980-3993. DOI: 10.7150/thno.41028.
NLM
Lv XF, Zhang YJ, Liu X, Zheng HQ, Liu CZ, Zeng XL, Li XY, Lin XC, Lin CX, Ma MM, Zhang FR, Shang JY, Zhou JG, Liang SJ, Guan YY. TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation. Theranostics 2020; 10(9):3980-3993. doi:10.7150/thno.41028. https://www.thno.org/v10p3980.htm
CSE
Lv XF, Zhang YJ, Liu X, Zheng HQ, Liu CZ, Zeng XL, Li XY, Lin XC, Lin CX, Ma MM, Zhang FR, Shang JY, Zhou JG, Liang SJ, Guan YY. 2020. TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation. Theranostics. 10(9):3980-3993.
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