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Increased intracellular Cl^- concentration in pulmonary arterial myocytes is associated with chronic hypoxic pulmonary hypertension.

ABSTRACT: 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% 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.

SUBMITTER: Sun H

PROVIDER: S-EPMC8526344 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Increased intracellular Cl- concentration in pulmonary arterial myocytes is associated with chronic hypoxic pulmonary hypertension.

Sun Hui H Paudel Omkar O Sham James S K JSK

American journal of physiology. Cell physiology 20210623 2

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 ...[more]

PMID: 34161154

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Project description:Platelet hyperactivity is essential for thrombus formation in coronary artery diseases (CAD). Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients with cystic fibrosis elevates intracellular Cl- levels ([Cl-]i) and enhanced platelet hyperactivity. In this study, we explored whether alteration of [Cl-]i has a pathological role in regulating platelet hyperactivity and arterial thrombosis formation. CFTR expression was significantly decreased, while [Cl-]i was increased in platelets from CAD patients. In a FeCl3-induced mouse mesenteric arteriole thrombosis model, platelet-specific Cftr-knockout and/or pre-administration of ion channel inhibitor CFTRinh-172 increased platelet [Cl-]i, which accelerated thrombus formation, enhanced platelet aggregation and ATP release, and increased P2Y12 and PAR4 expression in platelets. Conversely, Cftr-overexpressing platelets resulted in subnormal [Cl-]i, thereby decreasing thrombosis formation. Our results showed that clamping [Cl-]i at high levels or Cftr deficiency-induced [Cl-]i increasement dramatically augmented phosphorylation (Ser422) of serum and glucocorticoid-regulated kinase (SGK1), subsequently upregulated P2Y12 and PAR4 expression via NF-κB signaling. Constitutively active mutant S422D SGK1 markedly increased P2Y12 and PAR4 expression. The specific SGK1 inhibitor GSK-650394 decreased platelet aggregation in wildtype and platelet-specific Cftr knockout mice, and platelet SGK1 phosphorylation was observed in line with increased [Cl-]i and decreased CFTR expression in CAD patients. Co-transfection of S422D SGK1 and adenovirus-induced CFTR overexpression in MEG-01 cells restored platelet activation signaling cascade. Our results suggest that [Cl-]i is a novel positive regulator of platelet activation and arterial thrombus formation via the activation of a [Cl-]i-sensitive SGK1 signaling pathway. Therefore, [Cl-]i in platelets is a novel potential biomarker for platelet hyperactivity, and CFTR may be a potential therapeutic target for platelet activation in CAD.

Dataset Information

Increased intracellular Cl^- concentration in pulmonary arterial myocytes is associated with chronic hypoxic pulmonary hypertension.

Publications

Increased intracellular Cl<sup>-</sup> concentration in pulmonary arterial myocytes is associated with chronic hypoxic pulmonary hypertension.

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