Mitochondrial Aldehyde Dehydrogenase 2 Regulates Revascularization in Chronic Ischemia

Abstract

Objective— Revascularization is an essential process to compensate for cardiac underperfusion and, therefore, preserves cardiac function in the face of chronic ischemic injury. Recent evidence suggested a vital role of aldehyde dehydrogenase 2 (ALDH2) in cardiac protection after ischemia. This study was designed to determine whether ALDH2 regulates chronic ischemia−induced angiogenesis and to explore the underlying mechanism involved. Moreover, the clinical impact of the ALDH2 mutant allele on the development of coronary collateral circulation (CCC) was evaluated. Approach and Results— Mice limb ischemia was performed. Compared with wild-type, ALDH2 deletion significantly reduced perfusion recovery, small artery and capillary density, and increased muscle atrophy in this ischemic model. In vitro, ALDH2-knockdown reduced proliferation, migration and hypoxia triggered endothelial tube formation of endothelial cells, the effects of which were restored by ALDH2 transfection. Further examination revealed that ALDH2 regulated angiogenesis possibly through hypoxia-inducible factor-1α/vascular endothelial growth factor pathways. To further discern the role of ALDH2 deficiency in the function of bone marrow stem/progenitor cells, cross bone marrow transplantation was performed between wild-type and ALDH2-knockout mice. However, there was no significant improvement for wild-type bone marrow transplantation into knockout mice. ALDH2 genotyping was screened in 139 patients with chronic total occlusion recruited to Zhongshan Hospital (2011.10–2014.4). Patients with poor CCC (Rentrop 0–1; n=51) exhibited a higher frequency of the AA genotype than those with enriched CCC (Rentrop 2–3; n=88; 11.76% versus 1.14%; P =0 0.01). However, the AA group displayed less enriched CCC frequency in Logistic regression model when compared with the GG group (odds ratio=0.08; 95% confidence interval, 0.009–0.701; P =0 0.026). Furthermore, serum vascular endothelial growth factor level tended to be lower in patients with ALDH2 mutation. Conclusions— This study demonstrated that ALDH2 possesses an intrinsic capacity to regulate angiogenesis via hypoxia-inducible factor-1α and vascular endothelial growth factor. Patients with ALDH2-deficient genotype displayed a higher risk of developing poor CCC. Therapeutic individualization based on ALDH2 allele distribution may thus improve the therapeutic benefit, especially in the East Asian decedents.

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

“…ROS can inhibit ALDH2 dehydrogenase activity [57]. Data from recent studies have implicated ALDH2 and its polymorphisms in cardiovascular diseases [58], including coronary artery disease [59], ischemia-reperfusion injury [60], and diabetic cardiomyopathy [61]. Alda-1, the small molecule activator of ALDH2, reduces LPS-induced NF-κB p65 phosphorylation and nuclear translocation in human umbilical vein endothelial cells [62].…”

Mitochondrial Bioenergetics in the Metabolic Myopathy Accompanying Peripheral Artery Disease

“…In these studies, mitigation of mitochondrial oxidative stress by mitochondrial-targeted therapy improved mitochondrial function (Ryan et al, 2016a,b). In addition, mice deficient in mitochondrial aldehyde dehydrogenase 2, an enzyme responsible for toxic aldehyde clearance (such as 4-HNE), exhibited greater gastrocnemius muscle atrophy in response to chronic hindlimb ischemia compared to wild-type mice (Liu et al, 2015), further supporting a role for oxidative stress in the mitochondrial myopathy accompanying PAD.…”

Disruption of mitochondrial quality control in peripheral artery disease: New therapeutic opportunities

“…ALDH2 knockout mice subjected to hindlimb ischemia display slower recovery of limb perfusion and exacerbated myopathy compared to wild-type mice (107). Reduced blood perfusion in ALDH2 knockout mice was related to impaired angiogenesis (107). The impact of ALDH2 and aldehydic overload on intrinsic skeletal muscle changes in both PAD patients and hindlimb ischemia in rodents remains to be elucidated.…”