The Aldehyde Dehydrogenase 2 rs671 Variant Enhances Platelet Activation and Arterial Thrombosis

BACKGROUND: Acute myocardial infarction (AMI) caused by thrombosis is a major cause of mortality. A polymorphism in Aldh2 gene (rs671) is found in approximately 30% to 50% of East Asians, and it is a risk factor for AMI. This mutation impairs aldehyde dehydrogenase 2 (ALDH2) function, but the effect of ALDH2 on platelet activation and thrombosis is unknown. METHODS: Platelets were isolated from platelet-specific Aldh2 knockout ( Aldh2 -/- ) and ALDH2 E506K knock-in mice (which corresponds to human Aldh2 rs671 gene mutation), as well as from healthy human donors with the Aldh2 rs671. Arterial thrombosis was measured in a FeCl 3 -induced thrombosis mouse model. The efficacy of Alda-1, an ALDH2 activator, in mitigating thrombogenesis was measured in ALDH2 E506K mice. Using a murine model of myocardial infarction (MI) model, we analyzed the effects of platelet Aldh2 on micro-thrombosis and infarct expansion post-MI. In addition, we enrolled 118 patients of different Aldh2 rs671 genotypes (GG, GA, and AA) diagnosed with ST elevation myocardial infarction (STEMI) to analyze the association between rs671 genotype and platelet activation and thrombosis. RESULTS: Platelets from Aldh 2 -/- and ALDH2 E506K mice showed enhanced agonist induced aggregation, ATP release, integrin αIIbβ3 activation, P-selectin release, spreading, and clot retraction. Human platelets with the Aldh2 rs671 variant also exhibited increased activation. Mutation of Aldh2 or platelet-specific knockout of Aldh2 exacerbated thrombus formation in a mouse model of thrombosis. The ALDH2 activator, Alda-1, reduced thrombosis in ALDH2 E506K mice. We explored pathways mediating the effect of Aldh2 on platelet activation. We found that platelets lacking Aldh2 produced more reactive oxygen species (ROS) and less nitric oxide (NO) than wild-type platelets. Furthermore, platelets lacking Aldh2 are also more susceptible to activation by aldehydes. Additionally, platelets from mice lacking Aldh2 had increased elevated mitophagy and hyperactivity. ACAD10 mediated some of the effects of ALDH2 on mitophagy. Mice lacking Aldh2 had increased micro-thrombosis and myocardial infarct expansion. Finally, elevated platelet activation and thrombus markers were also observed in plasma from patients with STEMI patients who had the rs671 variant. CONCLUSIONS: The Aldh2 rs671 variant, which impairs ALDH2 function, increases platelet activation and thrombus formation in vivo through aldehyde accumulation and ROS buildup. Abnormal ACAD10 homeostasis might also contribute to this hyperactivity via enhancing platelet mitophagy. Our findings suggest the potential of ALDH2 as a novel antiplatelet target. Future studies are needed to explore the effects of more aggressive antiplatelet therapy for patients at risk of MI who carry the Aldh2 rs671 mutation.