Insight into the increased risk associated with CRISPR-generated African G6PD variant (N126D) in rat model of sugen-5416-induced pulmonary hypertension

Abstract

Pulmonary Hypertension (PH) is a cardiopulmonary disease associated with sustained increase in pulmonary arterial and right ventricular pressures, resulting in smooth muscle cell remodeling and the thickening of vasculature. Glucose-6-phosphate dehydrogenase (G6PD) is the rate limiting enzyme in the pentose phosphate pathway and is often associated with oxidative stress and the pulmonary vascular remodeling mechanism seen in PH. CRISPR-mediated single nucleotide polymorphism modeling was used to generate the African G6PD variant (N126D; G6PDN126D), which is an X-linked gene mutation resulting in a 20% decrease in G6PD activity and subsequent hypothesized increased risk of cardiovascular diseases for sub-Saharan individuals. The goal of this study was to determine the effects of the G6PDN126D variant using the Sugen-5416 (20 mg/kg in DMSO)/Normoxia (SU/NX)-induced PH rat model. Cardiac catheterization determined that the G6PDN126D variant-SU/Nx group had higher (G6PDN126D: 29.3 ± 5.2 vs WT: 19.5 ± 2.2; mmHg; p<0.05) mean right ventricle pressure and pulmonary artery remodeling as compared to the WT-SU/Nx group. Further, G6PDN126D variant-SU/Nx had lower nitric oxide levels (G6PDN126D: 10.6 vs WT: 13.6; mM/mg protein; p<0.05) and higher second messenger IP3 levels (G6PDN126D: 4.00 vs WT: 0.52; ng/mg protein; p<0.05) as compared to the WT-SU/Nx group. The data suggests that the African G6PD (N126D) mutation results in increased PH in rats and may be associated with increased risks of severe PH in the sub-Saharan population. These results imply more studies are required to develop personalized medicine for the treatment of PH. RO1HL132574 (SAG), RO1HL166546 (SAG), AHA Grant-in-Aid 17GRNT33670454 (SAG) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.