Introduction
Pulmonary hypertension (PH) is a multifactorial disease that is defined as sustained elevation of pulmonary arterial pressure (Farber & Loscalzo, 2004). The elevation of pulmonary arterial pressure increases right ventricular (RV) afterload, leading to heart failure and death (Runo & Loyd, 2003). The main vascular changes in PH are vasoconstriction, vascular cell proliferation, and thrombosis. Based on these findings, current standard of care is treatment with vasodilators. However, vasodilators such as endothelin receptor blockers, nitric oxide/nitrates, prostacyclin, and phosphodiesterase-5 inhibitors, fail to reverse vascular remodeling, and the long-term prognosis remains poor (Lajoie et al., 2016).
The pathogenesis of PH is still unclear. PH occurs under sustained environmental stress such as inflammation, shear stress, and hypoxia. This stress-stimuli contributes to the shifting of pulmonary vascular cells to hyper-proliferative and apoptotic-resistant phenotypes allowing abnormal vascular remodeling and PH development (Boucherat, Vitry, Trinh, Paulin, Provencher & Bonnet, 2017; D’Alessandro et al., 2018). Pulmonary vascular cells in patients with PH also undergo metabolic adaptation to support their high rate of proliferation or inadequate rates of mitotic fission. This metabolic shift, the Warburg phenomenon (Warburg, Wind & Negelein, 1927), is a failure of mitochondrial respiration and activation of aerobic glycolysis.
The pentose phosphate pathway (PPP) – a branch of glycolysis and a fundamental glucose metabolism pathway – is vital for cell growth and survival. Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the PPP. G6PD and the PPP generate pentose sugar, which is required for the de novo cellular synthesis of RNA and DNA, and NADPH, a key cofactor for reductive and anabolic reactions (Gupte & Wolin, 2012). Recently, we found that inhibition and knockdown of G6PD in lungs of a chronic hypoxia-induced PH mouse model reduced and reversed: 1) Warburg phenomenon, 2) epigenetic modification (DNA methylation), 3) maladaptive expression of genes that support pulmonary artery remodeling, and 4) PH and left heart dysfunction (Joshi et al., 2020). However, the role of G6PD in the pathogenesis of hypoxia+Sugen5416–induced PH is unknown. Furthermore, whether inhibition of G6PD reduces remodeling of pulmonary artery and PH in hypoxia+Sugen5416 mouse model remains to be determined. We hypothesized that G6PD is a safe pharmacotherapeutic target to reduce PH in hypoxia+Sugen5416 mouse model. Therefore, our objectives were to determine whether the inhibition of G6PD activity by pharmacologic or genetic manipulations would decrease differential DNA methylation and maladaptive gene expression in lungs and pulmonary vascular cells, reduce vascular remodeling, and normalize hemodynamics in models of chronic hypoxia- and hypoxia+Sugen5416-induced PH.