Aldehyde dehydrogenase 2 in cardiac protection: a new therapeutic target?
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is emerging as a key enzyme involved in cytoprotection in the heart. ALDH2 mediates both the detoxification of reactive aldehydes such as acetaldehyde and 4-hydroxy-2-nonenal and the bioactivation of nitroglycerin to nitric oxide. In addition, chronic nitrate treatment results in ALDH2 inhibition and contributes to nitrate tolerance. Our laboratory recently identified ALDH2 to be a key mediator of endogenous cytoprotection. We reported that ALDH2 is phosphorylated and activated by the survival kinase protein kinase C epsilon and found a strong inverse correlation between ALDH2 activity and infarct size. We also identified a small molecule ALDH2 activator which reduces myocardial infarct size induced by ischemia/reperfusion in vivo. In this review, we discuss evidence that ALDH2 is a key mediator of endogenous survival signaling in the heart, suggest possible cardioprotective mechanisms mediated by ALDH2 and discuss potential clinical implications of these findings.
Budas
Grant R
GR
Department of Chemical and Systems Biology, Stanford University School of Medicine, CA 94305-5174, USA.
Disatnik
Marie-Hélène
MH
Mochly-Rosen
Daria
D
D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D019610:Cytoprotection; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000201:enzymology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction
C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D011493:Protein Kinase C