Enhanced lung endothelial glycolysis is implicated in the development of severe pulmonary hypertension in type 2...

Metabolic abnormalities in pulmonary endothelial cells are implicated in pulmonary hypertension (PH) while increasing evidence shows the influence of diabetes on progressing PH. In this study, we examined the effect of type 2 diabetes on hypoxia-induced PH and investigated its molecular mechanisms using hypoxia-induced diabetic male mice. Chronic hypoxia led to a more severe PH in type 2 diabetic mice than in control mice. Next, we compared gene expression patterns in isolated pulmonary endothelial cells (MPECs) from control mice in normoxia (CN), diabetic mice in normoxia (DN), control mice exposed to hypoxia (CH), and diabetic mice exposed to hypoxia (DH). The results showed that expression levels of 27 mRNAs, out of 92 mRNAs, were significantly different among the four groups. Two glycolysis-related proteins, GAPDH and HK2, were increased in MPECs of DH mice compared with those in DN or CH mice. In addition, the levels of pyruvate and lactate (glycolysis end products) were significantly increased in MPECs of DH mice, but not in CH mice, compared with MPECs of CN mice. Augmentation of glycolysis by terazosin exacerbated hypoxia-induced PH in CH mice but not in DH mice. On the contrary, inhibiting GAPDH (a key enzyme of the glycolytic pathway) by koningic acid ameliorated hypoxia-induced PH in DH mice but had no effect in CH mice. These data suggest that enhanced glycolysis in diabetic mice is involved in severe hypoxia-induced PH, and glycolysis inhibition is a potential target to reduce the severe progression of PH in patients with diabetes.NEW & NOTEWORTHY Increasing evidence shows that diabetes exacerbates the progression of pulmonary hypertension; however, its molecular mechanisms are understudied. In this study, we revealed that augmented glycolysis in diabetic pulmonary endothelial cells is involved in the development of severe PH in diabetes. Inhibition of glycolysis could be a therapeutic strategy for treating pulmonary hypertension in patients with diabetes.