Document Detail

Downregulation of TMEM16A Calcium-Activated Chloride Channel Contributes to Cerebrovascular Remodeling during Hypertension through Promoting Basilar Smooth Muscle Cell Proliferation.
MedLine Citation:
PMID:  22215857     Owner:  NLM     Status:  Publisher    
BACKGROUND: The Ca(2+)-activated chloride channel (CaCC) plays an important role in a variety of physiological functions. In vascular smooth muscle cells, CaCC is involved in the regulation of agonist-stimulated contraction and myogenic tone. The physiological functions of CaCC in blood vessels are not fully revealed due to the lack of specific channel blockers and the uncertainty of its molecular identity. METHODS AND RESULTS: Whole-cell patch-clamp studies showed that knockdown of TMEM16A but not bestrophin-3 attenuated CaCC currents in rat basilar smooth muscle cells (BASMCs). The activity of CaCC in BASMCs isolated from 2-kidney, 2-clip renohypertensive rats were decreased and the CaCC activity negatively correlated with the blood pressure (n=25, p<0.0001) and the medial cross sectional area (n=24, p<0.0001) in basilar artery during hypertension. Both upregulation of CaMK II activity and downregulation of TMEM16A expression contributed to the reduction of CaCC in hypertensive basilar artery. Western blot results demonstrated that angiotensin II repressed TMEM16A expression in BASMCs (n=6, p<0.01). Knockdown of TMEM16A facilitated, whereas overexpression of TMEM16A inhibited, angiotensin II induced cell cycle transition and cell proliferation determined by flow cytometry and BrdU incorporation (n=6 in each group, p<0.05). TMEM16A affected cell cycle progression mainly through regulating the expression of cyclin D1 and cyclin E. CONCLUSIONS: TMEM16A CaCC is a negative regulator of cell proliferation. Downregulation of CaCC may play an important role in hypertension-induced cerebrovascular remodeling, suggesting modification of the activity of CaCC may be a novel therapeutic strategy for hypertension-associated cardiovascular diseases, such as stroke.
Mi Wang; Hui Yang; Ling-Yun Zheng; Zheng Zhang; Yong-Bo Tang; Guan-Lei Wang; Yan-Hua Du; Xiao-Fei Lv; Jie Liu; Jia-Guo Zhou; Yong-Yuan Guan
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-1-3
Journal Detail:
Title:  Circulation     Volume:  -     ISSN:  1524-4539     ISO Abbreviation:  -     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-1-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
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