Document Detail

Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension.
MedLine Citation:
PMID:  23034390     Owner:  NLM     Status:  MEDLINE    
Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca(2+) levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca(2+)-activated Cl- channels (Cl(Ca)), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of Cl(Ca) channels in PH was investigated using the monocrotaline (MCT)-induced PH model in the rat. Three weeks postinjection with a single dose of MCT (50 mg/kg ip), the animals developed right ventricular hypertrophy (heart weight measurements) and changes in pulmonary arterial flow (pulse-waved Doppler imaging) that were consistent with increased pulmonary arterial pressure and PH. Whole cell patch experiments revealed an increase in niflumic acid (NFA)-sensitive Ca(2+)-activated Cl(-) current [I(Cl(Ca))] density in PASMCs from large conduit and small intralobar pulmonary arteries of MCT-treated rats vs. aged-matched saline-injected controls. Quantitative RT-PCR and Western blot analysis revealed that the alterations in I(Cl(Ca)) were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for Cl(Ca) channels. The contraction to serotonin of conduit and intralobar pulmonary arteries from MCT-treated rats exhibited greater sensitivity to nifedipine (1 μM), an l-type Ca(2+) channel blocker, and NFA (30 or 100 μM, with or without 10 μM indomethacin to inhibit cyclooxygenases) or T16A(Inh)-A01 (10 μM), TMEM16A/Cl(Ca) channel inhibitors, than that of control animals. In conclusion, augmented Cl(Ca)/TMEM16A channel activity is a major contributor to the changes in electromechanical coupling of PA in this model of PH. TMEM16A-encoded channels may therefore represent a novel therapeutic target in this disease.
Abigail S Forrest; Talia C Joyce; Marissa L Huebner; Ramon J Ayon; Michael Wiwchar; John Joyce; Natalie Freitas; Alison J Davis; Linda Ye; Dayue D Duan; Cherie A Singer; Maria L Valencik; Iain A Greenwood; Normand Leblanc
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  303     ISSN:  1522-1563     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-02-26     Revised Date:  2013-12-18    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C1229-43     Citation Subset:  IM    
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MeSH Terms
Calcium Channel Blockers / pharmacology
Chloride Channels / agonists,  antagonists & inhibitors,  biosynthesis*,  physiology
Cyclooxygenase Inhibitors / pharmacology
Hypertension, Pulmonary / chemically induced,  drug therapy,  physiopathology*
Hypertrophy, Right Ventricular / chemically induced,  drug therapy,  physiopathology*
Indomethacin / pharmacology
Monocrotaline / toxicity
Muscle, Smooth, Vascular / drug effects,  physiopathology
Myocytes, Smooth Muscle / drug effects,  physiology
Nifedipine / pharmacology
Niflumic Acid / pharmacology
Patch-Clamp Techniques
Pulmonary Artery / drug effects,  physiopathology
Pyrimidines / pharmacology
Rats, Wistar
Serotonin / pharmacology
Thiazoles / pharmacology
Grant Support
3-R01-HL-075477-04S1/HL/NHLBI NIH HHS; 5-F31-HL-090023/HL/NHLBI NIH HHS; 5-P20-RR-15581/RR/NCRR NIH HHS; 5-R01-HL-075477/HL/NHLBI NIH HHS; P20 GM103440/GM/NIGMS NIH HHS; P20 RR016464/RR/NCRR NIH HHS; P20-RR-016464/RR/NCRR NIH HHS; PG/05/038//British Heart Foundation
Reg. No./Substance:
0/ANO1 protein, rat; 0/Calcium Channel Blockers; 0/Chloride Channels; 0/Cyclooxygenase Inhibitors; 0/Pyrimidines; 0/T16AInh-A01; 0/Thiazoles; 333DO1RDJY/Serotonin; 4U5MP5IUD8/Niflumic Acid; 73077K8HYV/Monocrotaline; I9ZF7L6G2L/Nifedipine; XXE1CET956/Indomethacin

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