Inhibition of Glucose-6-Phosphate Dehydrogenase 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 pathwayis 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 (N-[(3β,5α)-17-Oxoandrostan-3-yl]sulfamide;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, and decreased right ventricle pressures, 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.

Identification of Hypoxia Induced Metabolism Associated Genes in Pulmonary Hypertension

“…The interventions of specific enzymes to restore the abnormal metabolism open a new avenue for the treatment of PH. For example, inhibitor of glucose-6-phosphate dehydrogenase, a rate-limiting enzyme in pentose phosphate pathway, was reported to modulate DNA methylation and alleviate pulmonary artery remodeling (Kitagawa et al, 2021). Sphingosine kinases 1 (SphK1) is determinant for the synthesis of sphingosine-1-phosphate, an critical mediator for cell proliferation, migration and angiogenesis.…”

Glucose-6-phosphate dehydrogenase and MEG3 controls hypoxia-induced expression of serum response factor (SRF) and SRF-dependent genes in pulmonary smooth muscle cell

“…In a separated group, mice received daily subcutaneous injections of a novel G6PD inhibitor, N-[(3β,5α)-17-oxoandrostan-3-yl]sulfamide (4091; 1.5 mg kg −1 day −1 ) ( 32 ), for last 3 weeks of hypoxia. We have recently found that 4091 treatment inhibits G6PD activity in lungs of mice exposed to hypoxia ( 33 ). Mice were also intratracheally administered aerosolized AdGFP-G6PD-shRNA (IT-shG6PD), which reduces expression of G6PD, or AdGFP-scrambled-shRNA (given once a week) during weeks 3 and 4 ( 27 ).…”

Mitochondrial Metabolism, Redox, and Calcium Homeostasis in Pulmonary Arterial Hypertension

“…These results indicate that G6PD deficiency may protect against the development of PAH. Indeed, inhibition and knockdown of G6PD in chronic hypoxia-induced PAH and SuHx-PH rat models reverses the metabolic changes, epigenetic modification (DNA methylation), maladaptive expression of genes that contribute to PA remodeling, the formation of occlusive lesions, and RV pressure overload [ 70 , 71 , 72 , 73 ]. Protein kinase G1 (PKG1) signaling has a vital role in this process, as G6PD inhibition evokes PKG1α-dependent signaling, thereby mediating expression of contractile proteins, reducing Ang II-induced contraction and proinflammatory factor in PA response to hypoxia [ 66 , 74 , 75 ].…”