Inhibition of G6PD activity attenuates right ventricle pressure and hypertrophy elicited by VEGFR inhibitor + hypoxia

Abstract

Pulmonary hypertension (PH) is a disease of hyperplasia of pulmonary vascular cells. The pentose phosphate pathway (PPP) - a fundamental glucose metabolism pathway - is vital for cell growth. Because treatment for PH is inadequate, our goal was to determine whether inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, prevents maladaptive gene expression that promotes smooth muscle cell (SMC) growth, reduces pulmonary artery remodeling, and normalizes hemodynamics in experimental models of PH. PH was induced in mice by exposure to 10% oxygen (Hx) or weekly injection of vascular endothelial growth factor receptor blocker (Sugen5416 (SU); 20 mg.kg-1) during exposure to hypoxia (Hx+SU). A novel G6PD inhibitor (PDD4091;1.5 mg kg-1) was injected daily during exposure to Hx. We measured right ventricle (RV) pressure and left ventricle (LV) pressure-volume relationships, and gene expression in lungs of normoxic, Hx, and Hx+SU, and G6PD inhibitor-treated, mice. RV systolic and end-diastolic pressures were higher in Hx and Hx+SU than normoxic-control mice. Hx and Hx+SU decreased expression of epigenetic modifiers (writers and erasers), increased hypomethylation of the DNA, and induced aberrant gene expression in lungs. G6PD inhibition decreased maladaptive expression of genes and SMC growth, reduced pulmonary vascular remodeling, decreased RV pressures, and increased cardiac index, compared to untreated PH groups. Pharmacologic inhibition of G6PD activity, by normalizing activity of epigenetic modifiers and DNA methylation, efficaciously reduces RV pressure overload in Hx and Hx+SU mice, pre-clinical models of PH, appears to be a safe pharmacotherapeutic strategy. Significance Statement The results of this study demonstrated inhibition of a metabolic enzyme efficaciously reduces pulmonary hypertension. For first time, we show that a novel inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the fundamental pentose phosphate pathway, modulates DNA methylation and alleviates pulmonary artery remodeling and dilates pulmonary artery to reduce pulmonary hypertension.