Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 12 September 2008:
Vol. 321. no. 5895, pp. 1493 - 1495
DOI: 10.1126/science.1158554
Prev | Table of Contents | Next

Reports

Activation of Aldehyde Dehydrogenase-2 Reduces Ischemic Damage to the Heart

Che-Hong Chen,1 Grant R. Budas,1 Eric N. Churchill,1 Marie-Hélène Disatnik,1 Thomas D. Hurley,2 Daria Mochly-Rosen1*

There is substantial interest in the development of drugs that limit the extent of ischemia-induced cardiac damage caused by myocardial infarction or by certain surgical procedures. Here, using an unbiased proteomic search, we identified mitochondrial aldehyde dehydrogenase 2 (ALDH2) as an enzyme whose activation correlates with reduced ischemic heart damage in rodent models. A high-throughput screen yielded a small-molecule activator of ALDH2 (Alda-1) that, when administered to rats before an ischemic event, reduced infarct size by 60%, most likely through its inhibitory effect on the formation of cytotoxic aldehydes. In vitro, Alda-1 was a particularly effective activator of ALDH2*2, an inactive mutant form of the enzyme that is found in 40% of East Asian populations. Thus, pharmacologic enhancement of ALDH2 activity may be useful for patients with wild-type or mutant ALDH2 who are subjected to cardiac ischemia, such as during coronary bypass surgery.

1 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305–5174, USA.
2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

* To whom correspondence should be addressed. E-mail: mochly{at}stanford.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Aldehyde Dehydrogenase 2 Ameliorates Acute Cardiac Toxicity of Ethanol: Role of Protein Phosphatase and Forkhead Transcription Factor.
H. Ma, J. Li, F. Gao, and J. Ren (2009)
J. Am. Coll. Cardiol. 54, 2187-2196
   Abstract »    Full Text »    PDF »
Lessons From the Besotted Heart.
J. S. Karliner (2009)
J. Am. Coll. Cardiol. 54, 2197-2198
   Full Text »    PDF »
Beyond Reactive Oxygen Species: Aldehydes as Arbitrators of Alarm and Adaptation.
B. G. Hill and A. Bhatnagar (2009)
Circ. Res. 105, 1044-1046
   Full Text »    PDF »
Metabolic Remodeling Induced by Mitochondrial Aldehyde Stress Stimulates Tolerance to Oxidative Stress in the Heart.
J. Endo, M. Sano, T. Katayama, T. Hishiki, K. Shinmura, S. Morizane, T. Matsuhashi, Y. Katsumata, Y. Zhang, H. Ito, et al. (2009)
Circ. Res. 105, 1118-1127
   Abstract »    Full Text »    PDF »
Ischaemic preconditioning improves proteasomal activity and increases the degradation of {delta}PKC during reperfusion.
E. N. Churchill, J. C. Ferreira, P. C. Brum, L. I. Szweda, and D. Mochly-Rosen (2009)
Cardiovasc Res
   Abstract »    Full Text »    PDF »
Cardiovascular Consequences When Nitric Oxide and Lipid Signaling Converge.
V. Rudolph and B. A. Freeman (2009)
Circ. Res. 105, 511-522
   Abstract »    Full Text »    PDF »
Occult Cardiotoxicity--Toxic Effects on Cardiac Ischemic Tolerance.
E. Golomb, A. Nyska, and H. Schwalb (2009)
Toxicol Pathol 37, 572-593
   Abstract »    Full Text »    PDF »
Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans.
P. Wenzel, E. Schulz, T. Gori, M. A. Ostad, F. Mathner, S. Schildknecht, S. Gobel, M. Oelze, D. Stalleicken, A. Warnholtz, et al. (2009)
J. Pharmacol. Exp. Ther. 330, 63-71
   Abstract »    Full Text »    PDF »
Transgenic Overexpression of Aldehyde Dehydrogenase-2 Rescues Chronic Alcohol Intake-Induced Myocardial Hypertrophy and Contractile Dysfunction.
T. A. Doser, S. Turdi, D. P. Thomas, P. N. Epstein, S.-Y. Li, and J. Ren (2009)
Circulation 119, 1941-1949
   Abstract »    Full Text »    PDF »
Mechanistic Insights Into Nitrite-Induced Cardioprotection Using an Integrated Metabolomic/Proteomic Approach.
D. H. Perlman, S. M. Bauer, H. Ashrafian, N. S. Bryan, M. F. Garcia-Saura, C. C. Lim, B. O. Fernandez, G. Infusini, M. E. McComb, C. E. Costello, et al. (2009)
Circ. Res. 104, 796-804
   Abstract »    Full Text »    PDF »
Getting to the Heart of Proteomics.
P. Ping (2009)
N. Engl. J. Med. 360, 532-534
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)