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

Abstract

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.

From Rare Disorders of Kidney Tubules to Acute Renal Injury: Progress and Prospective

“…ALDH2 also potentially interacts with tubular transporters. Empagliflozin, an SGLT2 inhibitor, can mitigate ALDH2*2-induced endothelial cell dysfunction with the best docking pose with Alda-1 through the inhibition of Na + /H + exchanger 1 (NHE-1) and activation of AKT kinase and endothelial NO synthase pathways [ 96 ]. While tubular transporters play a significant role in rare tubulointerstitial diseases, there is little research investigating the involvement of ALDH2 in these conditions.…”

Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review)

“…Another study demonstrated that DAPA reduces cardiac endothelial dysfunction and microvascular injury by inhibition of the XO/sarco(endo) plasmic reticulum calcium ATPase 2/calmodulin-dependent kinase II/coffilin pathway in I/R injury mice ( 170 ). EMPA also improves endothelial cell dysfunction induced by a mutant aldehyde dehydrogenase 2 unable to metabolize acetaldehyde by inhibiting NHE1 and activating the AKT kinase and eNOS pathways ( 171 ). EMPA attenuates cardiac microvascular I/R injury through the activation of the AMP-activated protein kinase α1 (AMPKα1)/UNC-52-like kinase 1/FUN14 domain containing 1/mitophagy pathway ( 172 ).…”

Harnessing human genetics and stem cells for precision cardiovascular medicine

“…to find a compound that mitigates reactive oxidative species and boosts nitric oxide in iPSC-derived ECs with alcohol dehydrogenase 2 ( ALDH2∗2 rs671) variant, leading to drug repurposing of the sodium glucose cotransporter-2 inhibitor, empagliflozin. 64 …”

“…Thus, coronary EC dysfunction is a well-recognized maladaptive process in the development of CAD from early initiation to end-stage atherothrombotic complication. 64 Mutations in alcohol dehydrogenase 2 ( ALDH2 , also named ALDH2∗2 rs671), which are prevalent in East Asian populations and manifest as an “alcohol flush,” are also associated with an increased risk of CAD. 64 , 96 Using patient-derived ALDH2∗2 rs671 iPSC-ECs, Guo et al.…”

“… 64 Mutations in alcohol dehydrogenase 2 ( ALDH2 , also named ALDH2∗2 rs671), which are prevalent in East Asian populations and manifest as an “alcohol flush,” are also associated with an increased risk of CAD. 64 , 96 Using patient-derived ALDH2∗2 rs671 iPSC-ECs, Guo et al. found increased oxidative and inflammatory markers alongside functionally impaired nitric oxide production and tube formation capacity.…”