SGLT2 Inhibitor Ameliorates Endothelial Dysfunction Associated with the Common Alcohol Flushing Variant

The common aldehyde dehydrogenase 2 () alcohol flushing variant known as affects ∼8% of the world's population. Even in heterozygous carriers, this missense variant leads to a severe loss of ALDH2 enzymatic activity and has been linked to an increased risk of coronary artery disease (CAD). Endothelial cell (EC) dysfunction plays a determining role in all stages of CAD pathogenesis, including early-onset CAD. However, the contribution of to EC dysfunction and its relation to CAD are not fully understood. In a large genome-wide association study (GWAS) from Biobank Japan, was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carrying exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell-derived ECs (iPSC-ECs) and CRISPR-Cas9-corrected iPSC-ECs, we modeled -induced EC dysfunction in vitro, demonstrating an increase in oxidative stress and inflammatory markers and a decrease in nitric oxide (NO) production and tube formation capacity, which was further exacerbated by ethanol exposure. We subsequently found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin mitigated -associated EC dysfunction. Studies in knock-in mice further demonstrated that empagliflozin attenuated -mediated vascular dysfunction in vivo. Mechanistically, empagliflozin inhibited Na/H-exchanger 1 (NHE-1) and activated AKT kinase and endothelial NO synthase (eNOS) pathways to ameliorate -induced EC dysfunction. Together, our results suggest that induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD for carriers.