Role of ALDH2 in myocardial ischemia-reperfusion injury: using ALDH2 as a potential therapeutic target
TL;DR
The role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) is summarized as both an endogenous cardioprotective enzyme and a potential therapeutic target in myocardial I/R injury, and clinical translation will require genotype-informed patient stratification, optimization of ALDH2-targeted agonists, and careful timing around reperfusion.
Abstract
Myocardial ischemia-reperfusion (I/R) injury remains a major barrier to the full benefit of timely coronary reperfusion. This review summarizes the role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) as both an endogenous cardioprotective enzyme and a potential therapeutic target in myocardial I/R injury. During reperfusion, reactive oxygen species promote lipid peroxidation and the accumulation of cytotoxic aldehydes, particularly 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde. ALDH2 detoxifies these aldehydes and thereby modulates several injury pathways, including mitochondrial dysfunction, neutrophil extracellular trap formation, ferroptosis, apoptosis, necroptosis, and maladaptive autophagy. Experimental studies consistently indicate that ALDH2 deficiency aggravates infarct size, inflammatory injury, aldehyde overload, and adverse ventricular remodeling, whereas ALDH2 activation or overexpression confers protection. Clinical and genetic studies further suggest that the ALDH2 rs671/ALDH2*2 loss-of-function variant may influence myocardial infarction risk, reperfusion injury severity, and the response to cardioprotective strategies, especially in East Asian populations. However, the evidence remains largely preclinical, and clinical translation will require genotype-informed patient stratification, optimization of ALDH2-targeted agonists, careful timing around reperfusion, safety evaluation, and combination strategies with established reperfusion and cardioprotective approaches.