Inhibition of G6PD activity attenuates right ventricle pressure and hypertrophy elicited by VEGFR inhibitor + hypoxia
AffiliationPharmacology, New York Medical College, United States
MetadataShow full item record
AbstractPulmonary 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.
CitationKitagawa A, Jacob C, Jordan A, Waddell I, McMurtry IF, Gupte SA. Inhibition of G6PD activity attenuates right ventricle pressure and hypertrophy elicited by VEGFR inhibitor + hypoxia. J Pharmacol Exp Ther. 2021.
JournalJournal of Pharmacology and Experimental Therapeutics
- Hypoxic activation of glucose-6-phosphate dehydrogenase controls the expression of genes involved in the pathogenesis of pulmonary hypertension through the regulation of DNA methylation.
- Authors: Joshi SR, Kitagawa A, Jacob C, Hashimoto R, Dhagia V, Ramesh A, Zheng C, Zhang H, Jordan A, Waddell I, Leopold J, Hu CJ, McMurtry IF, D'Alessandro A, Stenmark KR, Gupte SA
- Issue date: 2020 Apr 1
- Pluripotent hematopoietic stem cells augment α-adrenergic receptor-mediated contraction of pulmonary artery and contribute to the pathogenesis of pulmonary hypertension.
- Authors: Hashimoto R, Lanier GM, Dhagia V, Joshi SR, Jordan A, Waddell I, Tuder R, Stenmark KR, Wolin MS, McMurtry IF, Gupte SA
- Issue date: 2020 Feb 1
- Impaired Pulmonary Arterial Vasoconstriction and Nitric Oxide-Mediated Relaxation Underlie Severe Pulmonary Hypertension in the Sugen-Hypoxia Rat Model.
- Authors: Christou H, Hudalla H, Michael Z, Filatava EJ, Li J, Zhu M, Possomato-Vieira JS, Dias-Junior C, Kourembanas S, Khalil RA
- Issue date: 2018 Feb
- Treatment of Pulmonary Hypertension With Angiotensin II Receptor Blocker and Neprilysin Inhibitor Sacubitril/Valsartan.
- Authors: Clements RT, Vang A, Fernandez-Nicolas A, Kue NR, Mancini TJ, Morrison AR, Mallem K, McCullough DJ, Choudhary G
- Issue date: 2019 Nov
- Carbonic anhydrase inhibition improves pulmonary artery reactivity and nitric oxide-mediated relaxation in sugen-hypoxia model of pulmonary hypertension.
- Authors: Christou H, Michael Z, Spyropoulos F, Chen Y, Rong D, Khalil RA
- Issue date: 2021 Jun 1