Hydrogen rescues vascular endothelial cells in obstructive sleep apnea-hypopnea syndrome by modulating nitric oxide.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a highly prevalent disorder characterized by chronic intermittent hypoxia (IH), which induces severe vascular endothelial dysfunction via oxidative stress and disruption of nitric oxide (NO) homeostasis, thereby elevating cardiovascular risk. Molecular hydrogen (H(2)) has emerged as a selective antioxidant with therapeutic potential, but its protective mechanisms against OSAHS-induced endothelial injury remain largely unexplored. This study aimed to investigate whether H(2) preserves endothelial function in the context of OSAHS by restoring NO bioavailability and to elucidate the underlying molecular pathways. METHODS: We employed a translational approach using both in vitro and in vivo models of IH. Human umbilical vein endothelial cells were subjected to IH cycles (1% O(2) for 5 min/21% O(2) for 10 min) for 24 hours with or without H(2)-rich medium (0.6 mM). In parallel, a rat model of OSAHS was established by exposing animals to IH (8% O(2) for 5 min/21% O(2) for 5 min, 8 hours/day) for 4 weeks, with a treatment group receiving daily 2% H(2) inhalation for 1 hour. We comprehensively assessed vascular pathology, oxidative stress markers [reactive oxygen species (ROS)/malondialdehyde (MDA)], key elements of the NO pathway [endothelial nitric oxide synthase (eNOS) phosphorylation, tetrahydrobiopterin (BH4) and its oxidized form BH2], inflammation [tumor necrosis factor-α (TNF-α), intercellular cell adhesion molecule-1 (ICAM-1)], and apoptosis. RESULTS: Our findings demonstrate that H(2) treatment significantly mitigated IH-induced oxidative stress, reducing ROS and MDA levels both in cells and aortic tissues. Crucially, H(2) restored NO bioavailability by enhancing eNOS phosphorylation at Ser1177 and preserving the critical BH4/BH2 ratio, thereby preventing eNOS uncoupling and superoxide overproduction. This was functionally confirmed by a marked improvement in endothelium-dependent vasodilation in H(2)-treated OSAHS rats. Furthermore, H(2) administration attenuated vascular remodeling, reducing medial thickening and collagen deposition, and suppressed the inflammatory response by downregulating TNF-α and ICAM-1 expression. Finally, H(2) significantly reduced endothelial apoptosis in aortic tissues. CONCLUSIONS: H(2) effectively alleviates OSAHS-related endothelial dysfunction by modulating redox homeostasis, recoupling eNOS to enhance NO production, and concurrently inhibiting inflammatory activation and apoptosis. These multifaceted protective effects highlight the significant therapeutic potential of H(2) as a novel adjunctive strategy for mitigating cardiovascular complications in in patients with OSAHS.