Abstract Body: Background: The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, present in nearly one-third of East Asians, results in reduced enzymatic capacity to detoxify reactive aldehydes such as 4-hydroxynonenal (4-HNE). This loss-of-function variant predisposes individuals to aldehyde accumulation, mitochondrial oxidative stress, and vascular dysfunction, particularly under ischemic conditions.
Objectives: To elucidate the mechanistic role of ALDH2 deficiency in ischemia-induced mitochondrial injury and endothelial dysfunction, and to assess its translational relevance in patients with peripheral artery disease (PAD).
Methods: ALDH2 deficiency was modeled using ALDH2 knock-in (KI) mice and siRNA-mediated ALDH2 knockdown in human umbilical vein endothelial cells (HUVECs). Hindlimb ischemia and oxygen–glucose deprivation (OGD) were employed to evaluate mitochondrial function, oxidative stress, and angiogenic capacity. Pharmacologic interventions included AD-5591, a selective ALDH2 activator, and a voltage-dependent anion channel (VDAC) inhibitor to block mitochondrial HSP60 release. Clinical relevance was examined in a prospective cohort of 227 PAD patients genotyped for ALDH2 rs671 and followed for major adverse limb events (MALEs).
Results: ALDH2 deficiency markedly impaired perfusion recovery, reduced capillary density, and exacerbated oxidative injury in ischemic tissues. In vitro, ALDH2 knockdown synergized with OGD to induce mitochondrial DNA depletion, membrane depolarization, excessive reactive oxygen species generation, and mitochondrial fragmentation. Transcriptomic profiling identified HSPD1 (HSP60) as a key downstream mediator; ALDH2 deficiency promoted cytosolic translocation of HSP60 and apoptotic signaling, both of which were attenuated by ALDH2 activation with AD-5591 or by VDAC inhibition. Clinically, PAD patients carrying ALDH2 rs671 variant alleles (G/A or A/A) exhibited significantly higher circulating oxidative stress biomarkers and an increased incidence of MALEs compared with wild-type carriers.
Conclusions: ALDH2 deficiency exacerbates ischemic vascular injury by amplifying HSP60-dependent mitochondrial oxidative stress and endothelial dysfunction. Targeting aldehyde detoxification through pharmacologic ALDH2 activation or modulation of mitochondrial HSP60 release represents a precision therapeutic strategy for ischemic vascular disease, particularly in East Asian populations.