Hydrogen alleviates right ventricular hypertrophy by inhibiting ferroptosis via restoration of the Nrf2/HO-1 signaling pathway.

BACKGROUND: Right ventricular hypertrophy (RVH) occurs because of volume or pressure overload within the right ventricular (RV) system. RVH is associated with complex pathological changes, including myocardial cell injury, apoptosis, myocardial fibrosis, neuroendocrine disturbances, and abnormal water and liquid metabolism. Ferroptosis, a novel type of iron-dependent cell death characterized by lipid peroxide accumulation, is an important mechanism of cardiomyocyte death. However, the role of ferroptosis in RVH has rarely been studied. We hypothesize that hydrogen (H(2)), an experimental medical gas with superior distribution characteristics, inhibits ferroptosis. AIM: To explore the protective effect of H(2) on RVH and the mechanism by which H(2) regulates ferroptosis. METHODS: An in vivo RVH rat model was induced by monocrotaline (MCT) in 30 male Sprague-Dawley rats. An H9C2 cell model was treated with angiotensin II to simulate pressure overload in the RV system in vitro. H(2) was administered to rats by inhalation (2% for 3 hours daily for 21 days) and added to the cell culture medium. The Nrf2 inhibitor ML385 (1 μM) was used to investigate anti-ferroptotic mechanisms. RESULTS: In MCT-treated rats, H(2) inhalation decreased RVH; the RV wall thickness decreased from 3.5 ± 0.3 mm to 2.8 ± 0.2 mm (P < 0.05) and the RV ejection fraction increased from 45 ± 3% to 52 ± 4% (P < 0.05). In H9C2 cells, H(2) alleviated hypertrophy. H(2) inhibited ferroptosis by modulating the iron content, oxidative stress, and ferroptosis-related proteins, thereby restoring the Nrf2/HO-1 signaling pathway. CONCLUSION: H(2) retards RVH by inhibiting ferroptosis via Nrf2/HO-1 restoration, suggesting a new treatment strategy.