Reduced Circulating HIF-1α, HIF-2α, HIF-3α, and VHL Levels in Patients With Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) involves complex vascular remodeling. The hypoxia-inducible factor (HIF) pathway is a central oxygen-sensing mechanism, but its circulating profile in PAH is poorly defined. This case-control study included 71 patients with PAH and 93 age- and sex-matched healthy controls. Serum levels of HIF-1α, HIF-2α, HIF-3α, and VHL were measured by ELISA. Serum levels of HIF-1α, HIF-2α, HIF-3α, and VHL were significantly lower in PAH patients compared with controls (all p < 0.05). HIF-1α demonstrated the highest diagnostic accuracy (AUC: 0.891; 95% CI: 0.836-0.947, p < 0.001). HIF-2α levels were significantly lower in patients in the intermediate-high risk category compared to the low-intermediate risk category (p = 0.0449). Circulating HIF pathway proteins are downregulated in PAH. These markers, particularly HIF-1α and HIF-2α, show potential for diagnostic screening and risk stratification, suggesting a systemic exhaustion of oxygen-sensing mechanisms.