hsa_circ_0001512 orchestrates endothelial dysfunction in obstructive sleep apnea by regulating the miR-4728-3p/MST4/ERK axis

Abstract Background Cardiovascular complications of obstructive sleep apnea (OSA) show marked vascular endotype heterogeneity that is not fully captured by the apnea-hypopnea index. We tested whether hsa_circ_0001512 acts as an intermittent hypoxia (IH)-responsive circRNA node that converts OSA-relevant stress into sustained endothelial dysfunction. Methods circRNA microarray profiling was performed in human umbilical vein endothelial cells exposed to IH or normoxia ( n = 3/group) and validated by qRT-PCR and back-splice junction sequencing. Candidate ceRNA interactions were interrogated by bioinformatic prediction, dual-luciferase reporter assays, gain- and loss-of-function perturbation, immunoblotting, and cytokine measurements. Translational relevance was assessed in PBMCs, serum cohorts, pooled serum-transfer assays, and a murine CIH model. Results IH induced the MCTP1-derived hsa_circ_0001512 after broad endothelial circRNA remodeling. hsa_circ_0001512 functionally sequestered miR-4728-3p, derepressed MST4, potentiated ERK1/2 phosphorylation, attenuated eNOS Ser1177 phosphorylation, and increased TNF-alpha, IL-1beta, and IL-6 release; miR-4728-3p restoration mitigated these phenotypes. In a clinical cohort of 30 patients with OSA and 30 controls, OSA status was independently associated with a concordant circ_0001512-high/miR-4728-3p-low/MST4-high signature and systemic cytokine elevation after adjustment for BMI, age, sex, and cardiometabolic comorbidities, and axis expression correlated with OSA severity. Pooled OSA serum recapitulated this phenotype in naive endothelial cells, and CIH induced concordant vascular pathway activation in vivo. Conclusions hsa_circ_0001512 is not merely an IH-induced transcript but a regulatory node that, based on the present experimental and adjusted observational data, plausibly contributes to OSA-related endothelial dysfunction through functional sequestration of miR-4728-3p and derepression of an MST4-associated ERK program. This back-splice-junction-specific axis represents a candidate vascular endotyping biomarker and a potential therapeutic target that merits prospective validation in OSA.