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Downregulation of Ca2+-activated Cl- channel TMEM16A in cirrhotic portal hypertension

[Speaker] Hisao Yamamura:1
[Co-author] Yoshiaki Suzuki:1, Yuji Imaizumi:1
1:Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan

Portal hypertension is a major complication in patients with chronic liver diseases and cirrhosis, but its pathogenic mechanism remains unclear. Vascular tone of portal vein smooth muscles is regulated by the activities of several ion channels including Ca2+-activated Cl- (ClCa) channel. TMEM16A is mainly responsible for ClCa channel conductance in vascular smooth muscle cells including portal vein smooth muscle cells (PVSMCs). Here, the functional expression of TMEM16A channels in portal hypertension was analyzed using two experimental animal models, bile duct ligation (BDL) mice with cirrhotic portal hypertension and partial portal vein ligation (PPVL) mice with idiopathic non-cirrhotic portal hypertension. Expression analyses revealed that TMEM16A was downregulated in BDL-PVSMCs by approximately 50% but not in PPVL-PVSMCs. Whole-cell ClCa currents were significantly reduced in BDL-PVSMCs compared to sham- and PPVL-PVSMCs. Portal vein smooth muscles from sham and PPVL mice showed spontaneous contractions which were sensitive to a specific inhibitor of TMEM16A, T16Ainh-A01. On the other hand, portal vein smooth muscles from BDL mice represented similar spontaneous contractions, however, the TMEM16A-mediated component was clearly attenuated. This TMEM16A downregulation was mimicked by the exposure to angiotensin II in normal PVSMCs. The angiotensin II-induced downregulation of TMEM16A was reversed by the treatment with an angiotensin II receptor blocker, candesartan. These results suggest that the reduced ClCa channel activity due to TMEM16A downregulation causes a lower membrane excitability of portal vein smooth muscles and results in preventing from development of portal hypertension.
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