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

Authors

Christina Signoretti, Department of Pharmacology New York Medical College Valhalla NY USA.
Shun Matsumura, Department of Pharmacology New York Medical College Valhalla NY USA.
Samuel Fatehi, Department of Pharmacology New York Medical College Valhalla NY USA.
Melinee D'Silva, Department of Pharmacology New York Medical College Valhalla NY USA.
Rajamma Mathew, Department of Medicine, Division of Pediatric Cardiology, Physiology New York Medical College Valhalla NY USA.
Francesca Cendali, Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora CO USA.
Angelo D'Alessandro, Department of Biochemistry and Molecular Genetics University of Colorado Anschutz Medical Campus Aurora CO USA.
S M. Alam, Department of Pathology, Microbiology, and Immunology (PMI) New York Medical College Valhalla NY USA.
Victor Garcia, Department of Pharmacology New York Medical College Valhalla NY USA.
Joseph M. Miano, Department of Medicine Vascular Biology Center, Medical College of Georgia at Augusta University Augusta GA USA.
Sachin A. Gupte, Department of Pharmacology New York Medical College Valhalla NY USA.

Author Type(s)

Student, Faculty, Resident/Fellow

DOI

10.1161/JAHA.123.035174

Journal Title

Journal of the American Heart Association

First Page

e035174

Document Type

Article

Publication Date

10-1-2024

Department

Pediatrics

Second Department

Pharmacology

Abstract

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) 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 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+SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca were increased in the lungs of G6PD+SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PD+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 increases inositol triphosphate-Ca 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.

Recommended Citation

Signoretti, C., Matsumura, S., Fatehi, S., D'Silva, M., Mathew, R., Cendali, F., D'Alessandro, A., Alam, S. M., Garcia, V., Miano, J. M., & Gupte, S. A. (2024). G6pd Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker-Induced Pulmonary Vascular Disease. Journal of the American Heart Association, 13 (19), e035174. https://doi.org/10.1161/JAHA.123.035174