PFKFB3 driven glycolysis mediates inflammation and Leukocyte Extravasation in CIH induced atherosclerosis

<bold>Rationale:</bold> Endothelial inflammation induced by CIH plays a prominent role in the initiation and development of OSA related cardiovascular diseases. <bold>Objectives:</bold> To assess metabolic alterations under CIH exposure to decipher the metabolic-inflammatory-axis in Endothelial cells (ECs). <bold>Methods:</bold> The project include inflammation and metabolic analyses of ECs under CIH exposure or plasma stimulation model, bioinformatics, CIH mouse models and assessment of OSA human subjects. <bold>Measurements and Main Results:</bold> Patients with severe OSA presented higher risk of higher cardiovascular risk, accompanied by increased abundance of plasma ICAM1 and IL6. In vivo models confirmed that CIH induced systemic inflammation and hypertension, and aggravates atherosclerosis. Transcriptome and in vitro analysis of CIH-stimulated ECs revealed upregulation of inflammatory responses comprising monocyte adhesion, coinciding with increased PFKFB3–mediated glycolysis. Endothelial-specific Pfkfb3 deficiency alleviates vascular inflammation and adhesion responses, thereby protects mice from CIH-induced vascular injury. Mechanistically, CIH induced up-regulated expression of HIF1A, which bound to the promoter region of PFKFB3, and in turn lead to PFKFB3-driven glycolysis and ECs inflammation. Moreover, pharmacological inhibition of PFKFB3 by 3PO or SAC or inhibition HIF1A by 2-ME reduced inflammatory and glycolysis signature of ECs in vivo and in vitro. <bold>Conclusions:</bold> These findings provide new insights into a metabolic-inflammatory-axis in ECs under CIH, and highlight the potential of targeting HIF1A/PFKFB3 axis in the treatment of OSA-related cardiovascular injuries.