title: Mitochondrial Aldehyde Dehydrogenase 2 Regulates Revascularization in Chronic Ischemia: Potential Impact on the Development of Coronary Collateral Circulation.
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.
  
  
  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.
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Xiangwei
authors: X
authors: Liu
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Xiaolei
authors: X
authors: Sun
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Hua
authors: H
authors: Liao
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Zhen
authors: Z
authors: Dong
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Jingjing
authors: J
authors: Zhao
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Hong
authors: H
authors: Zhu
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Peng
authors: P
authors: Wang
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Li
authors: L
authors: Shen
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Lei
authors: L
authors: Xu
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Xin
authors: X
authors: Ma
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Cheng
authors: C
authors: Shen
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Fan
authors: F
authors: Fan
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Cong
authors: C
authors: Wang
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Kai
authors: K
authors: Hu
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Yunzeng
authors: Y
authors: Zou
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Junbo
authors: J
authors: Ge
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.).
authors: Jun
authors: J
authors: Ren
authors: From the Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (X.L., H.Z., P.W., L.S., L.X., C.S., F.F., C.W., K.H., Y.Z., J.G., J.R., A.S.), Institute of Biomedical Science (X.S., L.X., X.M., Y.Z., J.G., A.S.), Department of Cardiology, Huashan Hospital (Z.D.), Fudan University, Shanghai, P.R. China; Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, University of Wyoming College of Health Sciences, Laramie (X.L., J.R.); Dongfang Hospital, Tongji University, Shanghai, P.R. China (H.L.); and Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China (J.Z.). sun.aijun@zs-hospital.sh.cn.
authors: Aijun
authors: A
authors: Sun
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003097:Collateral Circulation / Q000235:genetics; D003326:Coronary Circulation / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply*; D009154:Mutation; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011110:Polymorphism, Genetic; D011897:Random Allocation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: aldehyde dehydrogenase; coronary occlusion; endothelial progenitor cells; hypoxia-inducible factor; neovascularization