Alcohol consumption induced acute endothelial dysfunction in human ALDH2*2 carriers (RHI decreased to 1.48), an effect that was mitigated by SGLT2 inhibitors like empagliflozin in corresponding in vitro and in vivo models.
Observational (n=18)
Does empagliflozin improve endothelial dysfunction in models of the ALDH2*2 alcohol flushing variant?
SGLT2 inhibitors like empagliflozin may ameliorate endothelial dysfunction in ALDH2*2 carriers, suggesting a potential preventive strategy against CAD in this population.
Absolute Event Rate: 1.48% vs 1.97%
p-value: p=0.02
The common aldehyde dehydrogenase 2 ( ALDH2 ) alcohol flushing variant known as ALDH2*2 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 ALDH2*2 to EC dysfunction and its relation to CAD are not fully understood. In a large genome-wide association study (GWAS) from Biobank Japan, ALDH2*2 was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carrying ALDH2*2 exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell–derived ECs (iPSC-ECs) and CRISPR-Cas9–corrected ALDH2*2 iPSC-ECs, we modeled ALDH2*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 mitigated ALDH2*2 -associated EC dysfunction. Studies in ALDH2*2 knock-in mice further demonstrated that empagliflozin attenuated ALDH2*2 -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 ALDH2*2 -induced EC dysfunction. Together, our results suggest that ALDH2*2 induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD for ALDH2*2 carriers.
Guo et al. (Wed,) conducted a observational in ALDH2*2 alcohol flushing variant (n=18). Alcohol consumption in ALDH2*2 carriers vs. Alcohol consumption in wild-type ALDH2 carriers was evaluated on Reactive hyperemia index (RHI) as a measure of endothelial function (p=0.02). Alcohol consumption induced acute endothelial dysfunction in human ALDH2*2 carriers (RHI decreased to 1.48), an effect that was mitigated by SGLT2 inhibitors like empagliflozin in corresponding in vitro and in vivo models.