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

Background: Previous studies have found that hydrogen sulfide (H2S) has multiple func- tions such as anti-inflammatory, antioxidative in addition to biological effects among the var- ious organs. Exaggerated proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is a key component of vascular remodeling. We hypothe- sized that endogenous bioactive molecular known to suppress endoplasmic reticulum (ER) stress signaling, like H2S, will inhibit the disruption of the ER-mitochondrial unit and pre- vent/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). H2Ssignif- icantly 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 resis- tance, pulmonary artery remodeling and right ventricular hypertrophy, and improving func- tional 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 func- tion. Conclusion: H2S effectively inhibits hypoxia-induced increase in cell proliferation, migra- tion, 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