TY - JOUR
T1 - Increased intracellular Cl- concentration in pulmonary arterial myocytes is associated with chronic hypoxic pulmonary hypertension
AU - Sun, Hui
AU - Paudel, Omkar
AU - Sham, James S.K.
N1 - Publisher Copyright:
0363-6143/21 Copyright © 2021 the American Physiological Society
PY - 2021/8
Y1 - 2021/8
N2 - 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 þ -independent and Na þ -dependent Cl-/HCO3- exchangers. Exposure of rats to chronic hypoxia (10% O2, 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 ~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.
AB - 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 þ -independent and Na þ -dependent Cl-/HCO3- exchangers. Exposure of rats to chronic hypoxia (10% O2, 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 ~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.
KW - Cl- homeostasis
KW - Cl- transporters
KW - Intracellular Cl- concentration
KW - Pulmonary hypertension
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U2 - 10.1152/ajpcell.00172.2021
DO - 10.1152/ajpcell.00172.2021
M3 - Article
C2 - 34161154
AN - SCOPUS:85111553170
SN - 0363-6143
VL - 321
SP - C297-C307
JO - American Journal of Physiology - Cell Physiology
JF - American Journal of Physiology - Cell Physiology
IS - 2
ER -