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Papers of the Week

2023 Jan 25

Sci Transl Med



SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common alcohol flushing variant.


Guo H, Yu X, Liu Y, Paik DT, Justesen J M, Chandy M, Jahng JWS, Zhang T, Wu W, Rwere F, Zhao S R, Pokhrel S, Shivnaraine RV, Mukherjee S, Simon DJ, Manhas A, Zhang A, Chen C-H, Rivas MA, Gross ER, et al.
Sci Transl Med. 2023 Jan 25; 15(680):eabp9952.
PMID: 36696485.


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.