title: Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557-0573, USA.
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Forrest
authors.forename: Talia C
authors.initials: TC
authors.lastname: Joyce
authors.forename: Marissa L
authors.initials: ML
authors.lastname: Huebner
authors.forename: Ramon J
authors.initials: RJ
authors.lastname: Ayon
authors.forename: Michael
authors.initials: M
authors.lastname: Wiwchar
authors.forename: John
authors.initials: J
authors.lastname: Joyce
authors.forename: Natalie
authors.initials: N
authors.lastname: Freitas
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Davis
authors.forename: Linda
authors.initials: L
authors.lastname: Ye
authors.forename: Dayue D
authors.initials: DD
authors.lastname: Duan
authors.forename: Cherie A
authors.initials: CA
authors.lastname: Singer
authors.forename: Maria L
authors.initials: ML
authors.lastname: Valencik
authors.forename: Iain A
authors.initials: IA
authors.lastname: Greenwood
authors.forename: Normand
authors.initials: N
authors.lastname: Leblanc
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D002121:Calcium Channel Blockers / Q000494:pharmacology; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D009544:Niflumic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C552942:ANO1 protein, rat; D000075369:Anoctamin-1; D002121:Calcium Channel Blockers; D065101:Chloride Channel Agonists; D018118:Chloride Channels; D016861:Cyclooxygenase Inhibitors; D011743:Pyrimidines; C578466:T16AInh-A01; D013844:Thiazoles; D012701:Serotonin; D009544:Niflumic Acid; D016686:Monocrotaline; D009543:Nifedipine; D007213:Indomethacin