Abstract 056: Endothelial 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase, Isoform 3 (PFKFB3) Deficiency Inhibits Hypoxia-Induced Pulmonary Hypertension in Mice

Background: Pulmonary artery hypertension (PAH) is a severe proliferative disease characterized by the remodeling of small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and ultimately to right ventricular failure and death. Many studies have indicated that endothelial dysfunction is a key element in the pathogenesis of this disease. In this study, we investigated whether endothelial glycolysis plays a critical role in the development of hypoxia-induced PAH by knocking down endothelial PFKFB3 (encoding 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3), a critical regulator of glycolysis. Methods and Results: Immunostaining results showed that pulmonary artery endothelial PFKFB3 was increased in the lung of PAH patients. Mice deficient in endothelial Pfkfb3 showed decreased right ventricular systolic pressure, attenuated right ventricular hypertrophy and normal morphology of distal pulmonary arteries after four weeks of hypoxia compared with control mice. Furthermore, PFKFB3-deficient pulmonary arterial ECs secreted less growth factors, which ameliorated the proliferation of pulmonary artery smooth muscle cells. Additionally, the levels of endothelial derived inflammatory cytokines were also decreased. Besides, the inhibitory effect of endothelial Pfkfb3 supression on PAH formation were demonstrated in Sugen 5416/hypoxia rat pulmonary hypertension model with 3PO, a specific PFKFB3 inhibitor. Mechanistically, genetic deletion of PFKFB3 or 3PO treatment decreased the TNF-α induced NLRP3 inflammasome activation in pulmonary arterial ECs. Conclusions: Endothelial PFKFB3 inhibition is able to ameliorate the development of hypoxia-induced pulmonary hypertension.