Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 321, Issue 2, Pages C297-C307Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00172.2021
Keywords
Cl-; homeostasis; Cl-; transporters; intracellular Cl-; concentration; pulmonary hypertension
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Funding
- American Heart Association [11SDG7440069]
- National Institutes of Health [R01 HL-075134]
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This study provides evidence for altered intracellular Cl- homeostasis in PA smooth muscle cells associated with chronic hypoxic pulmonary hypertension, suggesting the important role of chloride transporters in regulating the Cl- concentration in pulmonary arterial smooth muscle cells.
Chloride channels play an important role in regulating smooth muscle contraction and proliferation, and contribute to the enhanced constriction of pulmonary arteries (PAs) in pulmonary hypertension (PH). The intracellular Cl- concentration ([Cl-](i)), tightly regulated by various Cl- transporters, determines the driving force for Cl- conductance, thereby the functional outcome of Cl- channel activation. This study characterizes for the first time the expression profile of Cl- transporters/exchangers in PA smooth muscle and provides the first evidence that the intracellular Cl- homeostasis is altered in PA smooth muscle cells (PASMCs) associated with chronic hypoxic PH (CHPH). Quantitative RT-PCR revealed that the endothelium-denuded intralobar PA of rats expressed Slc12a gene family encoded Na-K-2Cl cotransporter 1 (NKCC1), K-Cl cotransporters (KCC) 1, 3, and 4, and Slc4a gene family-encoded Na+-independent and Na+-dependent Cl-/HCO3- exchangers. Exposure of rats to chronic hypoxia (10% O-2, 3 wk) caused CHPH and selectively increased the expression of Cl--accumulating NKCC1 and reduced the Cl--extruding KCC4. The intracellular Cl- concentration ([Cl-](i)) averaged at 45 mM and 47 mM in normoxic PASMCs as determined by fluorescent indicator MEQ and by gramicidin-perforated patch-clamp technique, respectively. The ([Cl-](i) was increased by similar to 10 mM in PASMCs of rats with CHPH. Future studies are warranted to further establish the hypothesis that the altered intracellular Cl- homeostasis contributes to the pathogenesis of CHPH.
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