title: Characterization of the molecular mechanisms underlying increased ischemic damage in the aldehyde dehydrogenase 2 genetic polymorphism using a human induced pluripotent stem cell model system.
abstract: Nearly 8% of the human population carries an inactivating point mutation in the gene that encodes the cardioprotective enzyme aldehyde dehydrogenase 2 (ALDH2). This genetic polymorphism (ALDH2*2) is linked to more severe outcomes from ischemic heart damage and an increased risk of coronary artery disease (CAD), but the underlying molecular bases are unknown. We investigated the ALDH2*2 mechanisms in a human model system of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from individuals carrying the most common heterozygous form of the ALDH2*2 genotype. We showed that the ALDH2*2 mutation gave rise to elevated amounts of reactive oxygen species and toxic aldehydes, thereby inducing cell cycle arrest and activation of apoptotic signaling pathways, especially during ischemic injury. We established that ALDH2 controls cell survival decisions by modulating oxidative stress levels and that this regulatory circuitry was dysfunctional in the loss-of-function ALDH2*2 genotype, causing up-regulation of apoptosis in cardiomyocytes after ischemic insult. These results reveal a new function for the metabolic enzyme ALDH2 in modulation of cell survival decisions. Insight into the molecular mechanisms that mediate ALDH2*2-related increased ischemic damage is important for the development of specific diagnostic methods and improved risk management of CAD and may lead to patient-specific cardiac therapies.
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Antje D
authors.initials: AD
authors.lastname: Ebert
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kodo
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Liang
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Haodi
authors.initials: H
authors.lastname: Wu
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Huber
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Riegler
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Churko
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jaecheol
authors.initials: J
authors.lastname: Lee
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: de Almeida
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Lan
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Diecke
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Burridge
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Gold
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. joewu@stanford.edu mochly@stanford.edu.
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. joewu@stanford.edu mochly@stanford.edu.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D010641:Phenotype; D011110:Polymorphism, Genetic; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D055815:Young Adult
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D048031:JNK Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal