SGLT2 inhibitor ameliorates endothelial dysfunction associated with the commonALDH2alcohol flushing variant
Abstract
The common aldehyde dehydrogenase 2 (ALDH2) alcohol flushing variant known asALDH2*2affects ∼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 ofALDH2*2to EC dysfunction and its relation to CAD are not fully understood. In a large genome-wide association study (GWAS) from Biobank Japan,ALDH2*2was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carryingALDH2*2exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell–derived ECs (iPSC-ECs) and CRISPR-Cas9–correctedALDH2*2iPSC-ECs, we modeledALDH2*2-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 mitigatedALDH2*2-associated EC dysfunction. Studies inALDH2*2knock-in mice further demonstrated that empagliflozin attenuatedALDH2*2-mediated vascular dysfunction in vivo. Mechanistically,…
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