TMEM16A Contributes to Endothelial Dysfunction by Facilitating Nox2 NADPH Oxidase-Derived Reactive Oxygen Species Generation in Hypertension.
Ca2+-activated Cl-channels play a crucial role in various physiological processes. However, the role of TMEM16A in vascular endothelial dysfunction during hypertension is unclear. In this study, we investigated the specific involvement of TMEM16A in regulating endothelial function and blood pressure and the underlying mechanism. Reverse transcription-polymerase chain reaction, Western blotting, coimmunoprecipitation, confocal imaging, patch-clamp recordings, and TMEM16A endothelial-specific transgenic and knockout mice were used. We found that TMEM16A was expressed abundantly and functioned as a Ca2+-activated Cl-channel in endothelial cells. Angiotensin II induced endothelial dysfunction with an increase in TMEM16A expression. The knockout of endothelial-specific TMEM16A significantly lowered the blood pressure and ameliorated endothelial dysfunction in angiotensin II-induced hypertension, whereas the overexpression of endothelial-specific TMEM16A resulted in the opposite effects. These results were related to the increased reactive oxygen species production, Nox2-containing NADPH oxidase activation, and Nox2 and p22phox protein expression that were facilitated by TMEM16A on angiotensin II-induced hypertensive challenge. Moreover, TMEM16A directly bound with Nox2 and reduced the degradation of Nox2 through the proteasome-dependent degradation pathway. Therefore, TMEM16A is a positive regulator of endothelial reactive oxygen species generation via Nox2-containing NADPH oxidase, which induces endothelial dysfunction and hypertension. Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated diseases.
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.). mamm3@mail.sysu.edu.cn guanyy@mail.sysu.edu.cn.
Ming-Ming
MM
Ma
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Min
M
Gao
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Kai-Min
KM
Guo
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Mi
M
Wang
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Xiang-Yu
XY
Li
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Xue-Lin
XL
Zeng
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Lu
L
Sun
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Xiao-Fei
XF
Lv
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Yan-Hua
YH
Du
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Guan-Lei
GL
Wang
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Jia-Guo
JG
Zhou
From the Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China (M.-M.M., X.-Y.L., X.-L.Z., L.S., X.-F.L., Y.-H.D., G.-L.W., J.-G.Z., Y.-Y.G.); Department of Pharmacy, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (M.G.); Department of Obstetrics and Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, China (K.-M.G.); and Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China (M.W.).
Yong-Yuan
YY
Guan
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000075369:Anoctamin-1; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D000804:Angiotensin II; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D046988:Proteasome Endopeptidase Complex
NADPH oxidase; TMEM16A; angiotensin II; endothelial cells; hypertension; reactive oxygen species