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

Antje D. Ebert, Kazuki Kodo, Ping Liang, Haodi Wu, Bruno C. Huber, Johannes Riegler, Jared Churko, Jaecheol Lee, Patricia De Almeida, Feng Lan, Sebastian Diecke, Paul W. Burridge, Joseph D. Gold, Daria Mochly-Rosen, Joseph C. Wu

Research output: Contribution to journalArticle

48 Citations (Scopus)

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.

Original languageEnglish
Article number255ra130
JournalScience Translational Medicine
Volume6
Issue number255
DOIs
Publication statusPublished - 2014 Sep 24
Externally publishedYes

Fingerprint

Induced Pluripotent Stem Cells
Aldehyde Dehydrogenase
Genetic Polymorphisms
Cardiac Myocytes
Coronary Artery Disease
Cell Survival
Genotype
Poisons
Risk Management
Enzymes
Cell Cycle Checkpoints
Point Mutation
Aldehydes
Reactive Oxygen Species
Oxidative Stress
Up-Regulation
Apoptosis
Mutation
Wounds and Injuries
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. / Ebert, Antje D.; Kodo, Kazuki; Liang, Ping; Wu, Haodi; Huber, Bruno C.; Riegler, Johannes; Churko, Jared; Lee, Jaecheol; De Almeida, Patricia; Lan, Feng; Diecke, Sebastian; Burridge, Paul W.; Gold, Joseph D.; Mochly-Rosen, Daria; Wu, Joseph C.

In: Science Translational Medicine, Vol. 6, No. 255, 255ra130, 24.09.2014.

Research output: Contribution to journalArticle

Ebert, AD, Kodo, K, Liang, P, Wu, H, Huber, BC, Riegler, J, Churko, J, Lee, J, De Almeida, P, Lan, F, Diecke, S, Burridge, PW, Gold, JD, Mochly-Rosen, D & Wu, JC 2014, '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', Science Translational Medicine, vol. 6, no. 255, 255ra130. https://doi.org/10.1126/scitranslmed.3009027
Ebert, Antje D. ; Kodo, Kazuki ; Liang, Ping ; Wu, Haodi ; Huber, Bruno C. ; Riegler, Johannes ; Churko, Jared ; Lee, Jaecheol ; De Almeida, Patricia ; Lan, Feng ; Diecke, Sebastian ; Burridge, Paul W. ; Gold, Joseph D. ; Mochly-Rosen, Daria ; Wu, Joseph C. / 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. In: Science Translational Medicine. 2014 ; Vol. 6, No. 255.
@article{dab5062b380742fd989b0b7979b76cbb,
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.",
author = "Ebert, {Antje D.} and Kazuki Kodo and Ping Liang and Haodi Wu and Huber, {Bruno C.} and Johannes Riegler and Jared Churko and Jaecheol Lee and {De Almeida}, Patricia and Feng Lan and Sebastian Diecke and Burridge, {Paul W.} and Gold, {Joseph D.} and Daria Mochly-Rosen and Wu, {Joseph C.}",
year = "2014",
month = "9",
day = "24",
doi = "10.1126/scitranslmed.3009027",
language = "English",
volume = "6",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "255",

}

TY - JOUR

T1 - 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

AU - Ebert, Antje D.

AU - Kodo, Kazuki

AU - Liang, Ping

AU - Wu, Haodi

AU - Huber, Bruno C.

AU - Riegler, Johannes

AU - Churko, Jared

AU - Lee, Jaecheol

AU - De Almeida, Patricia

AU - Lan, Feng

AU - Diecke, Sebastian

AU - Burridge, Paul W.

AU - Gold, Joseph D.

AU - Mochly-Rosen, Daria

AU - Wu, Joseph C.

PY - 2014/9/24

Y1 - 2014/9/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84908377652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908377652&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.3009027

DO - 10.1126/scitranslmed.3009027

M3 - Article

VL - 6

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 255

M1 - 255ra130

ER -