SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant

Area of Science:

• Cardiovascular Research
• Genetics
• Pharmacology

Background:

• The ALDH2*2 variant, common in East Asian populations, impairs alcohol metabolism and is linked to increased coronary artery disease (CAD) risk.
• Endothelial cell (EC) dysfunction is a key factor in CAD pathogenesis, but its specific link to ALDH2*2 remains unclear.

Purpose of the Study:

• To investigate the role of the ALDH2*2 variant in endothelial cell dysfunction and its association with CAD.
• To explore the therapeutic potential of SGLT2 inhibitors in mitigating ALDH2*2-associated EC dysfunction.

Main Methods:

• Genome-wide association study (GWAS) identified ALDH2*2 as a strong CAD risk factor.
• In vitro studies using induced pluripotent stem cell-derived ECs (iPSC-ECs) and CRISPR-Cas9 correction to model ALDH2*2 effects.
• In vivo studies using ALDH2*2 knock-in mice.
• Assessment of endothelial function, oxidative stress, inflammation, nitric oxide (NO) production, and vascular reactivity.

Main Results:

• ALDH2*2 carriers exhibited impaired vasodilation and EC dysfunction, characterized by increased oxidative stress, inflammation, and reduced NO production.
• Ethanol exposure exacerbated ALDH2*2-associated EC dysfunction.
• SGLT2 inhibitors (e.g., empagliflozin) effectively mitigated ALDH2*2-induced EC dysfunction in vitro and vascular dysfunction in vivo.
• Empagliflozin acted by inhibiting NHE-1 and activating AKT/eNOS pathways.

Conclusions:

• The ALDH2*2 variant directly contributes to endothelial cell dysfunction, a mechanism underlying increased CAD risk.
• SGLT2 inhibitors represent a promising therapeutic strategy for preventing CAD in individuals with the ALDH2*2 variant.