G6PD Orchestrates Genome-Wide DNA Methylation and Gene Expression in the Vascular Wall

Background G6PD (glucose‐6‐phosphate‐dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension‐associated vascular remodeling. Here, we investigated the role of an X‐linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub‐Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer. Methods and Results CRISPR‐Cas9 genome editing was used to generate the G6pd variant (N126D; G6pd N126D ) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen‐5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pd N126D rats and their wild‐type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PD N126D +SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca 2+ were increased in the lungs of G6PD N126D +SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PD N126D +SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor‐1, thrombin‐antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C‐C motif] ligand), CCL5, and CCL7. Conclusions Our results suggest G6PD N126D increases inositol triphosphate‐Ca 2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU‐treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker‐induced pulmonary hypertension in those carrying this G6PD variant.

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Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

Thomas,

Palczewski,

Kuschman

et al. 2024

Preprint

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DNA methylation at cytosine bases of eukaryotic DNA (5-methylcytosine, 5mC) is a heritable epigenetic mark that can regulate gene expression in health and disease. Enzymes that metabolize 5mC have been well-characterized, yet the discovery of endogenously produced signaling molecules that regulate DNA methyl-modifying machinery have not been described. Herein, we report that the free radical signaling molecule nitric oxide (NO) can directly inhibit the Fe(II)/2-OG-dependent DNA demethylases ten-eleven translocation (TET) and human AlkB homolog 2 (ALKBH2). Physiologic NO concentrations reversibly inhibited TET and ALKBH2 demethylase activity by binding to the mononuclear non-heme iron atom which formed a dinitrosyliron complex (DNIC) preventing cosubstrates (2-OG and O2) from binding. In cancer cells treated with exogenous NO, or cells endogenously synthesizing NO, there was a global increase in 5mC and 5-hydroxymethylcytosine (5hmC) in DNA, the substrates for TET, that could not be attributed to increased DNA methyltransferase activity. 5mC was also elevated in NO-producing cell-line-derived mouse xenograft and patient-derived xenograft tumors. Genome-wide DNA methylome analysis of cells chronically treated with NO (10 days) demonstrated enrichment of 5mC and 5hmC at gene-regulatory loci which correlated to changes in the expression of NO-regulated tumor-associated genes. Regulation of DNA methylation is distinctly different from canonical NO signaling and represents a novel epigenetic role for NO.

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G6PD Orchestrates Genome-Wide DNA Methylation and Gene Expression in the Vascular Wall

Cited by 3 publications

References 74 publications

Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats

Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats

G6pd ^N126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker‐Induced Pulmonary Vascular Disease

Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

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G6PD Orchestrates Genome-Wide DNA Methylation and Gene Expression in the Vascular Wall

Cited by 3 publications

References 74 publications

Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats

Loss-of-function G6PD variant moderated high-fat diet-induced obesity, adipocyte hypertrophy, and fatty liver in male rats

G6pd N126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker‐Induced Pulmonary Vascular Disease

Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

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G6pd ^N126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker‐Induced Pulmonary Vascular Disease