Redox Regulation of Ion Channels and Receptors in Pulmonary Hypertension

Abstract

Significance: Pulmonary hypertension (PH) is characterized by elevated vascular resistance due to vasoconstriction and remodeling of the normally low-pressure pulmonary vasculature. Redox stress contributes to the pathophysiology of this disease by altering the regulation and activity of membrane receptors, K⁺ channels, and intracellular Ca²⁺ homeostasis. Recent Advances: Antioxidant therapies have had limited success in treating PH, leading to a growing appreciation that reductive stress, in addition to oxidative stress, plays a role in metabolic and cell signaling dysfunction in pulmonary vascular cells. Reactive oxygen species generation from mitochondria and NADPH oxidases has substantial effects on K⁺ conductance and membrane potential, and both receptor-operated and store-operated Ca²⁺ entry. Critical Issues: Some specific redox changes resulting from oxidation, S-nitrosylation, and S-glutathionylation are known to modulate membrane receptor and ion channel activity in PH. However, many sites of regulation that have been elucidated in nonpulmonary cell types have not been tested in the pulmonary vasculature, and context-specific molecular mechanisms are lacking. Future Directions: Here, we review what is known about redox regulation of membrane receptors and ion channels in PH. Further investigation of the mechanisms involved is needed to better understand the etiology of PH and develop better targeted treatment strategies.

Keywords: NADPH oxidase; calcium homeostasis; hypoxia; potassium channels; reactive oxygen species; reductive stress.

FIG. 1.

Redox stress contributes to chronic hypoxia-induced pulmonary hypertension by promoting both vasoconstriction and vascular remodeling.

FIG. 2.

Both reductive and oxidative stress contribute to cellular ROS production. Reductive stress, characterized by abnormally high levels of reducing equivalents, contributes to oxidative stress by inducing mitochondrial dysfunction and activating NOX. G6PD, glucose-6-phosphate dehydrogenase; GPx1, glutathione peroxidase isoform 1; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; H₂O₂, hydrogen peroxide; NAD(P)⁺/NAD(P)H, nicotinamide adenine dinucleotide (phosphate); NOX, NADPH oxidase; ROS, reactive oxygen species; SOD, superoxide dismutase.

FIG. 3.

Hypoxia alters PASMC energy metabolism. Hypoxia increases glucose uptake and promotes glycolysis and the pentose phosphate pathway in the cytoplasm, yielding excess NADH and NADPH. This metabolic shift comes at the expense of oxidative phosphorylation in the mitochondria; yet high levels of NADH result in electron leakage and superoxide formation at complexes I and III of the electron transport chain. Hypoxia-augmented pathways and metabolites are in bold. 6PG, 6-phosphogluconate; CoQ, coenzyme Q; Cyt, cytochrome c; FAD/FADH₂, flavin adenine dinucleotide oxidized/reduced; GLUT, glucose transporter; G6P, glucose-6-phosphate; HK, hexokinase; IMS, intermembrane space; MM, mitochondrial matrix; NADH, nicotinamide adenine dinucleotide; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PASMC, pulmonary arterial smooth muscle cell; TCA, tricarboxylic acid.

FIG. 4.

Summary of redox regulation of membrane receptors. See text for details. ⊕, activation; ø, inhibition; EGFR, epidermal growth factor receptor; GPCR, G protein-coupled receptor; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidyl-inositol-3-kinase; PKC, protein kinase C; PTP, protein tyrosine phosphatase; S-ON, S-nitrosylation.

FIG. 5.

Summary of redox regulation of K⁺ channels. See text for details. ⊕, activation; ø, inhibition; E_m, membrane potential; MetSO₍₂₎, methionine oxidation; SO_(n)H, sulfenic acid modulation; SSG, S-glutathionylation; VGCC, voltage-gated Ca²⁺ channels.

FIG. 6.

Summary of redox regulation of Ca²⁺ homeostasis. See text for details. ⊕, activation; ø, inhibition; ASIC1, acid-sensing ion channel 1; DAG, diacylglycerol; IP₃(R), inositol triphosphate (receptor); ORAI1, calcium release-activated calcium modulator 1; RISP, Rieske iron-sulfur protein; RyR, ryanodine receptor; SERCA, sarco-/endoplasmic reticulum calcium ATPase; SOC/ROC, store-operated channels/receptor-operated channels; SR, sarcoplasmic reticulum; STIM1, stromal interaction molecule 1; TRPC, transient receptor potential channel.