| Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension. | |
| | |
MedLine Citation:
|
PMID: 23034390 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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:
|
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: 2013-04-16 |
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 |
Affiliation:
|
Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada 89557-0573, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals 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 Male 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 Rats, Wistar Serotonin / pharmacology Thiazoles / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
|
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 |
| Chemical | |
Reg. No./Substance:
|
0/ANO1 protein, rat; 0/Calcium Channel Blockers; 0/Chloride Channels; 0/Cyclooxygenase Inhibitors; 0/Pyrimidines; 0/T16AInh-A01; 0/Thiazoles; 21829-25-4/Nifedipine; 315-22-0/Monocrotaline; 4394-00-7/Niflumic Acid; 50-67-9/Serotonin; 53-86-1/Indomethacin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Calcium-binding protein 39 facilitates molecular interaction between Ste20p proline alanine-rich kin...
Next Document: miR-141 as a regulator of the mitochondrial phosphate carrier (Slc25a3) in the type 1 diabetic heart...