Targeting ALDH2 in Atherosclerosis: Molecular Mechanisms and Therapeutic Opportunities

  • Sai Ma
  • Feng Cao
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1193)


Aldehyde dehydrogenase 2 (ALDH2) is an important member of the functional aldehyde dehydrogenases (ALDHs) family in human beings, playing a fundamental role in the detoxification of acetaldehyde and other aldehydes. In recent years, a number of researches have given attention to the association between ALDH2 and atherosclerosis, which provided insights on targeting ALDH2 for therapeutic intervention of atherosclerosis. In this review, these inspiring studies will be discussed, and the clinical implications and concerns will be expounded.


ALDH2 (aldehyde dehydrogenase 2) Atherosclerosis Cardioprotection Molecular mechanisms Clinical implications 





Aldehyde dehydrogenase 2


Aldehyde dehydrogenases


Apolipoprotein E knockout


Atherosclerotic cardiovascular disease


Coronary artery bypass grafting


Cardiovascular disease




Endoplasmic reticulum


High-density lipoprotein cholesterol


Human umbilical vein endothelial cells

I/R injury

Ischemia-reperfusion injury


Low-density lipoprotein cholesterol




Myocardial infarction


  1. 1.
    Kucharska-Newton A, Griswold M, Yao ZH, Foraker R, Rose K, Rosamond W et al (2017) Cardiovascular disease and patterns of change in functional status over 15 years: findings from the Atherosclerosis Risk in Communities (ARIC) Study. J Am Heart Assoc 6(3)Google Scholar
  2. 2.
    Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S (2016) Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ Res 118(4):535–546CrossRefGoogle Scholar
  3. 3.
    Barquera S, Pedroza-Tobias A, Medina C, Hernandez-Barrera L, Bibbins-Domingo K, Lozano R et al (2015) Global overview of the epidemiology of atherosclerotic cardiovascular disease. Arch Med Res 46(5):328–338CrossRefGoogle Scholar
  4. 4.
    Levenson JW, Skerrett PJ, Gaziano JM (2002) Reducing the global burden of cardiovascular disease: the role of risk factors. Prev Cardiol 5(4):188–199CrossRefGoogle Scholar
  5. 5.
    Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A (2010) Growing epidemic of coronary heart disease in low- and middle-income countries. Curr Probl Cardiol 35(2):72–115CrossRefGoogle Scholar
  6. 6.
    Solanki A, Bhatt L, Johnston T (2018) Evolving targets for the treatment of atherosclerosis. Pharmacol Ther 187:1–12CrossRefGoogle Scholar
  7. 7.
    Chiang CP, Jao SW, Lee SP, Chen PC, Chung CC, Lee SL et al (2012) Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer. Alcohol 46(1):37–49CrossRefGoogle Scholar
  8. 8.
    Vasiliou V (1997) Aldehyde dehydrogenase genes. Adv Exp Med Biol 414:595–600PubMedPubMedCentralGoogle Scholar
  9. 9.
    Vasiliou V, Nebert DW (2005) Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum Genomics 2(2):138–143PubMedPubMedCentralGoogle Scholar
  10. 10.
    Parrilla R, Okawa K, Lindros KO, Zimmerman UJ, Kobayashi K, Williamson JR (1974) Functional compartmentation of acetaldehyde oxidation in rat liver. J Biol Chem 249(15):4926–4933PubMedPubMedCentralGoogle Scholar
  11. 11.
    Eriksson CJ, Marselos M, Koivula T (1975) Role of cytosolic rat liver aldehyde dehydrogenase in the oxidation of acetaldehyde during ethanol metabolism in vivo. Biochem J 152(3):709–712CrossRefGoogle Scholar
  12. 12.
    Zhu Q, He G, Wang J, Wang Y, Chen W (2017) Pretreatment with the ALDH2 agonist Alda-1 reduces intestinal injury induced by ischaemia and reperfusion in mice. Clin Sci 131(11):1123–1136CrossRefGoogle Scholar
  13. 13.
    Chen C, Ferreira J, Gross E, Mochly-Rosen D (2014) Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev 94(1):1–34CrossRefGoogle Scholar
  14. 14.
    Stickel F, Moreno C, Hampe J, Morgan M (2017) The genetics of alcohol dependence and alcohol-related liver disease. J Hepatol 66(1):195–211CrossRefGoogle Scholar
  15. 15.
    Baig M, Adil M, Khan R, Dhadi S, Ahmad K, Rabbani G et al (2017) Enzyme targeting strategies for prevention and treatment of cancer: implications for cancer therapy. Semin Cancer BiolGoogle Scholar
  16. 16.
    Panisello-Roselló A, Lopez A, Folch-Puy E, Carbonell T, Rolo A, Palmeira C et al (2018) Role of aldehyde dehydrogenase 2 in ischemia reperfusion injury: an update. World J Gastroenterol 24(27):2984–2994CrossRefGoogle Scholar
  17. 17.
    Li C, Li X, Chang Y, Zhao L, Liu B, Wei S et al (2018) Aldehyde dehydrogenase-2 attenuates myocardial remodeling and contractile dysfunction induced by a high-fat diet. Cell Physiol Biochem 48(5):1843–1853CrossRefGoogle Scholar
  18. 18.
    Sung Y, Lu C, Lee J, Hung Y, Hu C, Jeng J et al (2016) Homozygous ALDH2*2 is an independent risk factor for ischemic stroke in Taiwanese men. Stroke 47(9):2174–2179CrossRefGoogle Scholar
  19. 19.
    Zhang X, Ye Y, Wang Y, Liu F, Liu X, Hu B et al (2015) Aldehyde dehydrogenase 2 genetic variations may increase susceptibility to Parkinson’s disease in Han Chinese population. Neurobiol Aging 36(9):2660. e9–13CrossRefGoogle Scholar
  20. 20.
    Beretta M, Gorren AC, Wenzl MV, Weis R, Russwurm M, Koesling D et al (2010) Characterization of the East Asian variant of aldehyde dehydrogenase-2: bioactivation of nitroglycerin and effects of Alda-1. J Biol Chem 285(2):943–952CrossRefGoogle Scholar
  21. 21.
    Gross E, Zambelli V, Small B, Ferreira J, Chen C, Mochly-Rosen D (2015) A personalized medicine approach for Asian Americans with the aldehyde dehydrogenase 2*2 variant. Annu Rev Pharmacol Toxicol 55:107–127CrossRefGoogle Scholar
  22. 22.
    Mizuno Y, Harada E, Morita S, Kinoshita K, Hayashida M, Shono M et al (2015) East Asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome. Circulation 131(19):1665–1673CrossRefGoogle Scholar
  23. 23.
    Gong D, Zhang L, Zhang Y, Wang F, Zhou X, Sun H (2019) East Asian variant of aldehyde dehydrogenase 2 is related to worse cardioprotective results after coronary artery bypass grafting. Interact Cardiovasc Thorac Surg 28(1):79–84CrossRefGoogle Scholar
  24. 24.
    Zhang Y, Ren J (2011) ALDH2 in alcoholic heart diseases: molecular mechanism and clinical implications. Pharmacol Ther 132(1):86–95CrossRefGoogle Scholar
  25. 25.
    Doser T, Turdi S, Thomas D, Epstein P, Li S, Ren J (2009) Transgenic overexpression of aldehyde dehydrogenase-2 rescues chronic alcohol intake-induced myocardial hypertrophy and contractile dysfunction. Circulation 119(14):1941–1949CrossRefGoogle Scholar
  26. 26.
    Liu B, Zhang R, Wei S, Yuan Q, Xue M, Hao P et al (2018) ALDH2 protects against alcoholic cardiomyopathy through a mechanism involving the p38 MAPK/CREB pathway and local renin-angiotensin system inhibition in cardiomyocytes. Int J Cardiol 257:150–159CrossRefGoogle Scholar
  27. 27.
    Ueta C, Campos J, Albuquerque R, Lima V, Disatnik M, Sanchez A et al (2018) Cardioprotection induced by a brief exposure to acetaldehyde: role of aldehyde dehydrogenase 2. Cardiovasc Res 114(7):1006–1015CrossRefGoogle Scholar
  28. 28.
    Kang P, Wu W, Tang Y, Xuan L, Guan S, Tang B et al (2016) Activation of ALDH2 with low concentration of ethanol attenuates myocardial ischemia/reperfusion injury in diabetes rat model. Oxidative Med Cell Longev 2016:6190504Google Scholar
  29. 29.
    Stachowicz A, Olszanecki R, Suski M, Wiśniewska A, Totoń-Żurańska J, Madej J et al (2014) Mitochondrial aldehyde dehydrogenase activation by Alda-1 inhibits atherosclerosis and attenuates hepatic steatosis in apolipoprotein E-knockout mice. J Am Heart Assoc 3(6):e001329CrossRefGoogle Scholar
  30. 30.
    Lapenna D, Ciofani G, Ucchino S, Giamberardino M, Di Ilio C, Cuccurullo F (2015) Reactive aldehyde-scavenging enzyme activities in atherosclerotic plaques of cigarette smokers and nonsmokers. Atherosclerosis 238(2):190–194CrossRefGoogle Scholar
  31. 31.
    Yang MY, Wang YB, Han B, Yang B, Qiang YW, Zhang Y et al (2018) Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells. Acta Pharmacol Sin 39(1):48–58CrossRefGoogle Scholar
  32. 32.
    Pan C, Xing JH, Zhang C, Zhang YM, Zhang LT, Wei SJ et al (2016) Aldehyde dehydrogenase 2 inhibits inflammatory response and regulates atherosclerotic plaque. Oncotarget 7(24):35562–35576CrossRefGoogle Scholar
  33. 33.
    Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K et al (2015) Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol 66(5):495–507CrossRefGoogle Scholar
  34. 34.
    Patel K, Strong A, Tohyama J, Jin X, Morales C, Billheimer J et al (2015) Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis. Circ Res 116(5):789–796CrossRefGoogle Scholar
  35. 35.
    Rader D, Hovingh G (2014) HDL and cardiovascular disease. Lancet 384(9943):618–625CrossRefGoogle Scholar
  36. 36.
    Hao P, Xue L, Wang X, Chen Y, Wang J, Ji W et al (2010) Association between aldehyde dehydrogenase 2 genetic polymorphism and serum lipids or lipoproteins: a meta-analysis of seven East Asian populations. Atherosclerosis 212(1):213–216CrossRefGoogle Scholar
  37. 37.
    Newman WP, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL et al (1986) Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The Bogalusa Heart Study. N Engl J Med 314(3):138–144CrossRefGoogle Scholar
  38. 38.
    Kaplan H, Thompson R, Trumble B, Wann L, Allam A, Beheim B et al (2017) Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. Lancet 389(10080):1730–1739CrossRefGoogle Scholar
  39. 39.
    Takagi S, Baba S, Iwai N, Fukuda M, Katsuya T, Higaki J et al (2001) The aldehyde dehydrogenase 2 gene is a risk factor for hypertension in Japanese but does not alter the sensitivity to pressor effects of alcohol: the Suita study. Hypertens Res 24(4):365CrossRefGoogle Scholar
  40. 40.
    Chang YC, Yen-Feng C, I-Te L, Low-Tone H, Yi-Jen H, Hsiung CA et al (2012) Common ALDH2 genetic variants predict development of hypertension in the SAPPHIRe prospective cohort: gene-environmental interaction with alcohol consumption. BMC Cardiovasc Disord 12(1):58CrossRefGoogle Scholar
  41. 41.
    Brandt M, Wenzel P (2018) Alcohol puts the heart under pressure: acetaldehyde activates a localized renin angiotensin aldosterone system within the myocardium in alcoholic cardiomyopathy. Int J Cardiol 257:220–221CrossRefGoogle Scholar
  42. 42.
    Hellström E, Tottmar O (1982) Acute effects of ethanol and acetaldehyde on blood pressure and heart rate in disulfiram-treated and control rats. Pharmacol Biochem Behav 17(6):1103–1109CrossRefGoogle Scholar
  43. 43.
    Satoh Y, Ide Y, Sugano T, Koda K, Momose Y, Tagami M (2008) Hypotensive and hypertensive effects of acetaldehyde on blood pressure in rats. Nihon Arukoru Yakubutsu Igakkai Zasshi 43(3):188–193PubMedPubMedCentralGoogle Scholar
  44. 44.
    Chen Z, Stamler JS (2006) Bioactivation of nitroglycerin by the mitochondrial aldehyde dehydrogenase. Trends Cardiovasc Med 16(8):259–265CrossRefGoogle Scholar
  45. 45.
    Chen Z, Foster MW, Zhang J, Mao L, Rockman HA, Kawamoto T et al (2005) An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. Proc Natl Acad Sci U S A 102(34):12159–12164CrossRefGoogle Scholar
  46. 46.
    Kollau A, Hofer A, Russwurm M, Koesling D, Keung WM, Schmidt K et al (2005) Contribution of aldehyde dehydrogenase to mitochondrial bioactivation of nitroglycerin: evidence for the activation of purified soluble guanylate cyclase through direct formation of nitric oxide. Biochem J 385(Pt 3):769–777CrossRefGoogle Scholar
  47. 47.
    Zhong W, Zhang W, Li Q, Xie G, Sun Q, Sun X et al (2015) Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice. J Hepatol 62(6):1375–1381CrossRefGoogle Scholar
  48. 48.
    Hua Y, Chen H, Zhao X, Liu M, Jin W, Yan W et al (2018) Alda-1, an aldehyde dehydrogenase-2 agonist, improves long-term survival in rats with chronic heart failure following myocardial infarction. Mol Med Rep 18(3):3159–3166PubMedPubMedCentralGoogle Scholar
  49. 49.
    Chen C, Cruz L, Mochly-Rosen D (2015) Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo. Proc Natl Acad Sci U S A 112(10):3074–3079CrossRefGoogle Scholar
  50. 50.
    Pan G, Deshpande M, Pang H, Palaniyandi S (2018) Precision medicine approach: Empagliflozin for diabetic cardiomyopathy in mice with aldehyde dehydrogenase (ALDH) 2*2 mutation, a specific genetic mutation in millions of East Asians. Eur J Pharmacol 839:76–81CrossRefGoogle Scholar
  51. 51.
    Xu F, Chen YG, Geng YJ, Zhang H, Jiang CX, Sun Y et al (2007) The polymorphism in acetaldehyde dehydrogenase 2 gene, causing a substitution of Glu > Lys(504), is not associated with coronary atherosclerosis severity in Han Chinese. Tohoku J Exp Med 213(3):215–220CrossRefGoogle Scholar
  52. 52.
    Zhang Y, Wang C, Zhou J, Sun A, Hueckstaedt LK, Ge J et al (2017) Complex inhibition of autophagy by mitochondrial aldehyde dehydrogenase shortens lifespan and exacerbates cardiac aging. Biochim Biophys Acta Mol basis Dis 1863(8):1919–1932CrossRefGoogle Scholar
  53. 53.
    Zhang Y, Mi SL, Hu N, Doser TA, Sun A, Ge J et al (2014) Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function. Free Radic Biol Med 71:208–220CrossRefGoogle Scholar
  54. 54.
    Dassanayaka S, Zheng Y, Gibb A, Cummins T, McNally L, Brittian K et al (2018) Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload. Redox Biol 17:440–449CrossRefGoogle Scholar
  55. 55.
    Guo Y, Yu W, Sun D, Wang J, Li C, Zhang R et al (2015) A novel protective mechanism for mitochondrial aldehyde dehydrogenase (ALDH2) in type i diabetes-induced cardiac dysfunction: role of AMPK-regulated autophagy. Biochim Biophys Acta 1852(2):319–331CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Sai Ma
    • 1
    • 2
  • Feng Cao
    • 1
  1. 1.Department of Cardiology, & National Clinical Research Center of Geriatrics DiseaseChinese PLA General HospitalBeijingChina
  2. 2.Jinling Hospital Department of CardiologyNanjing University, School of MedicineNanjingChina

Personalised recommendations