The Role of Cariporide in Protecting Saphenous Vein among Different Aldehyde Dehydrogenase Genotypes

Lin, Yi; Luo, Chentao; Shi, Yunqing; Ma, Ru; Qi, Xun; Ding, Wenjun

doi:10.1159/000506071

Cited by 1 publication

(1 citation statement)

References 21 publications

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“…However, cariporide failed in phase 3 clinical trials for CAD patients due to increased mortality ( 75 ). More recently, one study showed that cariporide could improve vascular function ex vivo in saphenous veins from ALDH2*2 carriers ( 76 ), suggesting that NHE-1 may be a potential therapeutic target for follow-up studies in either specific patient populations or with other small molecules.…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitor ameliorates endothelial dysfunction associated with the commonALDH2alcohol flushing variant

Guo

Liu

et al. 2023

Sci. Transl. Med.

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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.

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Section: Discussionmentioning

confidence: 99%