Cullin 2 Elevates the Warburg Effect to Accelerate the Development of Hypoxic Pulmonary Hypertension

Pulmonary arterial hypertension is a disease characterized by abnormally high pulmonary arterial blood pressures caused by a variety of heterogeneous diseases and different pathogenetic mechanisms. This study establishes a hypoxic pulmonary hypertension (HPH) mouse model, revealing cullin 2 (CUL2)'s critical role in disease pathogenesis. Hypoxia up-regulates CUL2 in HPH lungs, whereas CUL2 knockdown alleviates the Warburg effect, right ventricular dysfunction, and pulmonary fibrosis. In vitro, CUL2 depletion suppresses proliferation, adhesion, and tube formation in hypoxic pulmonary arterial endothelial cells. Mechanistically, CUL2 enhances glycolysis by up-regulating lactate dehydrogenase A (LDHA)/phosphofructokinase, liver type (PFKL), and their overexpression rescues CUL2-silencing effects. Furthermore, hypoxia-induced proline hydroxylase 2 (PHD2) down-regulation stabilizes hypoxia-inducible factor-1α (HIF-1α), which directly binds the CUL2 promoter to enhance its expression. These findings unveil a novel PHD2/HIF-1α/CUL2 axis that promotes vascular remodeling via glycolysis, offering a potential therapeutic target for pulmonary arterial hypertension. In conclusion, this work demonstrated that under hypoxia condition, PHD2-mediated hydroxylation of HIF-1α was blocked and the expression of HIF-1α was elevated in HPH mice. High levels of HIF-1α elevated the transcription and expression of CUL2 and increased the Warburg effect, thereby accelerating HPH development.