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.