Disrupted erythrocyte S1P-eNOS axis promotes hypoxia, hypertension and fibrosis in obstructive sleep apnoea-hypopnoea syndrome

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ID: 320093
2026
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Abstract
BACKGROUND AND AIMS: Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) has emerged as a global epidemic with profound cardiovascular and renal consequences, yet its early pathogenic mechanisms remain poorly understood. Whether red blood cells (RBCs) act as the primary hypoxia sensor that transduces intermittent apnoea into irreversible outcomes remains enigmatic. This study aims to define the pathogenic nature of RBCs during the progression of OSAHS with a goal of identifying early biomarkers and targeted treatments to prevent detrimental outcomes. METHODS: A large OSAHS cohort and matched controls underwent quantification of RBC O2 off-loading capability and nitric oxide (NO) bioactivity. Untargeted metabolomics and [13C6, 15N4] arginine flux mapping identified specific metabolic pathway bottlenecks. The effect of OSAHS erythrocytes on endothelial function was evaluated by measuring acetylcholine-induced vasodilation in rat aortic rings incubated with the erythrocytes and perfused in a microfluidic system. Erythrocyte-specific sphingosine kinase-1 knockout mice (eSphK1-/-) and controls were exposed to chronic intermittent hypoxia (CIH). Therapeutic studies include a preclinical manipulation with the arginase inhibitor nor-NOHA, and a pilot continuous positive airway pressure (CPAP) observational study. RESULTS: OSAHS patients display dysfunctional RBCs with reduced O2 delivery and NO bioactivity alongside excessive oxidative stress, driven by impaired glucose and arginine metabolism. Moreover, arginine metabolism is preferentially channelled into ornithine and urea rather than NO production due to reduced endothelial nitric oxide synthase (eNOS) activity. Dysfunctional RBC-mediated blunted endothelium-dependent vasodilation is rescued by co-infusion of sodium nitroprusside (SNP) and pretreatment with S1P or nor-NOHA. These RBC anomalies correlate with peripheral hypoxia, hypertension, and metabolic disorders in patients and precede measurable hypertension and tissue damage in a CIH-exposed OSAHS murine model. Preclinically, nor-NOHA restores RBC-NO bioactivity and O2 delivery, normalizes blood pressure, and prevents tissue fibrosis. A three-circulating-metabolite fingerprint, including sphingosine, S1P, and arginine, is validated as an early and sensitive biomarker for its diagnosis and stratifies OSAHS severity. Genetically, CIH-challenged eSphK1-/- mice exhibit decreased eNOS activity and O2 offload capacity, severe tissue hypoxia, hypertension, and fibrosis. Mechanistically, this study revealed that decreased intracellular S1P and AMPK activity underlie reduced eNOS activation in RBCs of OSAHS by blocking its trafficking from the membrane to the cytosol and phosphorylation. In contrast, CPAP-treated patients exhibited lower erythrocyte dysfunction and arginine and sphingolipid metabolic impairment compared to untreated OSAHS patients. CONCLUSIONS: Altogether, this study demonstrates that OSAHS is a systemic RBC disease in which S1P-mediated O2 delivery and eNOS trafficking act as the master toggle between physiological O2 delivery and hypoxic vasculopathy. Circulating S1P, sphingosine, and arginine configuration constitute a sensitive metabolic signature enabling early diagnoses, while pharmacological or CPAP-mediated repair of the RBC S1P-eNOS axis offers precision cardiovascular and renal protection upstream of irreversible vascular injury.
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Authors Yuhua Fan, Chang‐Han Chen, Cheng Luo, Simin Zhou, Hongan Lu, Fang Yu, Zhiying He, Yue Wang, Yuyu Chou, Yanxiu Li, Xianjing Feng, Tingting Xie, Li Wan, Xi Long, Yue Wang, D A Luo, Yuexiang Qin, Xin Zhang, Jia Liu, Ruiwen Mao, Zhiyu Yang, Yu Zhang, Rodney E. Kellems, Donghai Huang, Yang Xia
Journal european heart journal
Year 2026
DOI
10.1093/eurheartj/ehag405
URL
https://doi.org/10.1093/eurheartj/ehag405
Keywords Keywords not found

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