H₂S attenuates endoplasmic reticulum stress in hypoxia-induced pulmonary artery hypertension

Background: Previous studies have found that hydrogen sulfide (H₂S) has multiple functions such as anti-inflammatory, antioxidative in addition to biological effects among the various organs. Exaggerated proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is a key component of vascular remodeling. We hypothesized that endogenous bioactive molecular known to suppress endoplasmic reticulum (ER) stress signaling, like H₂S, will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse pulmonary arterial hypertension (PAH). Methods and results: A hypoxic model was established with PASMCs to investigate the possible role of H₂S in PAH. Effects of H₂S on proliferation of PASMCs were evaluated by CCK-8 and EdU assay treated with or without GYY4137 (donor of H₂S). H₂S significantly inhibited hypoxia-induced increase in PASMCs proliferation in a dose-dependent manner. H₂S by intraperitoneal injection with rats both prevented and reversed chronic hypoxia-induced pulmonary hypertension in rats, decreasing pulmonary vascular resistance, pulmonary artery remodeling and right ventricular hypertrophy, and improving functional capacity without affecting systemic hemodynamic. Exogenous H₂S suppressed ER stress indexes in vivo and in vitro, decreased activating transcription factor 6 activation, and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function.Conclusion: H₂S effectively inhibits hypoxia-induced increase in cell proliferation, migration, and oxidative stress in PASMCs, and NOX-4 might be the underlying mechanism of PAH. Attenuating ER stress with exogenous H₂S may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.