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Sci Transl Med. 2014 Sep 24;6(255):255ra130. doi: 10.1126/scitranslmed.3009027.

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.

Author information

1
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.
2
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.
3
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.
4
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. joewu@stanford.edu mochly@stanford.edu.
6
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.

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.

PMID:
25253673
PMCID:
PMC4215699
DOI:
10.1126/scitranslmed.3009027
[Indexed for MEDLINE]
Free PMC Article

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