Mediterranean G6PD Variant Mitigates Expression of DNA Methyltransferases and Right Heart Pressure in Experimental Model of Pulmonary Hypertension

Authors

Christina Jacob, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Atsushi Kitagawa, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Christina Signoretti, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Monika Dzieciatkowska, Department of Biochemistry & Molecular Genetics, School of Medicine, University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, USA.
Angelo D'Alessandro, Department of Biochemistry & Molecular Genetics, School of Medicine, University of Colorado Denver - Anschutz Medical Campus, Aurora, Colorado, USA.
Aaditya Gupte, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Shakib Hossain, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Catherine A. D'Addario, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Rakhee Gupte, Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
Sachin A. Gupte, Department of Pharmacology, New York Medical College, Valhalla, New York, USA. Electronic address: s_gupte@nymc.edu.Follow

Author Type(s)

Faculty

DOI

10.1016/j.jbc.2022.102691

Journal Title

The Journal of Biological Chemistry

First Page

102691

Document Type

Article

Publication Date

12-1-2022

Department

Pharmacology

Abstract

DNA methylation potentially contributes to the pathogenesis of pulmonary hypertension (PH). However, the role of DNA methyltransferases (DNMTs: 1, 3a, and 3b), the epigenetic writers, in modulating DNA methylation observed in PH remains elusive. Our objective was to determine DNMT activity and expression in the lungs of experimental rat models of PH. Because the activity of DNMTs is metabolically driven, another objective was to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in regulating DNMT expression and activity in the lungs of novel loss-of-function Mediterranean G6PD variant (G6PD) rats. As outlined for modeling PH, rats injected with sugen5416 (SU) were placed in a hypoxia (Hx) chamber set at 10% oxygen for 3 weeks and then returned to normoxia (Nx) for 5 weeks (SU/Hx/Nx). Rats kept in atmospheric oxygen and treated with SU were used as controls. We assessed the activity and expression of DNMTs in the lungs of rats exposed to SU/Hx/Nx. WT rats exposed to SU/Hx/Nx developed hypertension and exhibited increased DNMT activity and Dnmt1 and Dnmt3b expression. In G6PD rats, which developed less of a SU/Hx/Nx-induced increase in right ventricle pressure and hypertrophy than WT rats, we observed a diminished increase in expression and activity of DNMTs, DNA hypomethylation, increased histone acetylation and methylation, and increased expression of genes encoding NOS3 and SOD2-vascular-protective proteins. Collectively, increased DNMTs contribute to reduced expression of protective genes and to the pathogenesis of SU/Hx/Nx-induced experimental PH. Notably, G6PD regulates the expression of DNMTs and protective proteins in the lungs of hypertensive rats.

Recommended Citation

Jacob, C., Kitagawa, A., Signoretti, C., Dzieciatkowska, M., D'Alessandro, A., Gupte, A., Hossain, S., D'Addario, C. A., Gupte, R., & Gupte, S. A. (2022). Mediterranean G6PD Variant Mitigates Expression of DNA Methyltransferases and Right Heart Pressure in Experimental Model of Pulmonary Hypertension. The Journal of Biological Chemistry, 298 (12), 102691. https://doi.org/10.1016/j.jbc.2022.102691