Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension
| Autor: | Alison J. Davis, John Joyce, Talia C. Joyce, Abigail S. Forrest, Maria L. Valencik, Iain A. Greenwood, Linda Ye, Ramon J. Ayon, Dayue Darrel Duan, Marissa L. Huebner, Normand Leblanc, Cherie A. Singer, Michael Wiwchar, Natalie Freitas |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Serotonin medicine.medical_specialty Patch-Clamp Techniques Nifedipine Physiology Hypertension Pulmonary Indomethacin Myocytes Smooth Muscle chemistry.chemical_element Pulmonary Artery Calcium Muscle Smooth Vascular Chloride Channels Internal medicine medicine.artery medicine Animals Myocyte Cyclooxygenase Inhibitors Rats Wistar Chloride Channel Agonists Anoctamin-1 Chloride channel activity Monocrotaline Hypertrophy Right Ventricular Niflumic acid Niflumic Acid Articles Cell Biology Calcium Channel Blockers medicine.disease Pulmonary hypertension Rats Thiazoles Pyrimidines Endocrinology chemistry Anesthesia Pulmonary artery Chloride channel medicine.drug |
| Zdroj: | American Journal of Physiology-Cell Physiology. 303:C1229-C1243 |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00044.2012 |
| Popis: | Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca2+ levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca2+-activated Cl− channels (ClCa), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of ClCa 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 Ca2+-activated Cl− current [ ICl(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 ICl(Ca) were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for ClCa 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 Ca2+ channel blocker, and NFA (30 or 100 μM, with or without 10 μM indomethacin to inhibit cyclooxygenases) or T16AInh-A01 (10 μM), TMEM16A/ClCa channel inhibitors, than that of control animals. In conclusion, augmented ClCa/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. |
| Databáze: | OpenAIRE |
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