Editors' ChoiceCardiovascular Physiology

Personalized Heart Healing

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Sci. Signal.  30 Sep 2014:
Vol. 7, Issue 345, pp. ec268
DOI: 10.1126/scisignal.2005957

In poetry, we welcome assaults to the heart that leave one breathless. But depriving actual heart tissue of oxygen—through decreased blood flow—can cause irreparable damage. The human genome contains ALDH2, a gene that encodes the heart-protective metabolic enzyme aldehyde dehydrogenase 2. But ~8% of the population carries an inactivating gene polymorphism (ALDH2*2) that has been linked to enhanced severity of damage from cardiac ischemia—a shortage in the heart’s oxygen supply—and an increased risk of coronary artery disease. Ebert et al. investigate the mechanisms underlying these ALDH2*2-associated maladies using a human cellular model of the ALDH2*2 genotype made with induced pluripotent stem cell–derived cardiomyocytes generated from patient fibroblasts. The authors found that ALDH2 promoted cell survival by limiting oxidative stress, a circuit that was dysfunctional in ALDH2*2 cells, resulting in cell cycle arrest and enhanced apoptosis in ALDH2*2 cardiomyocytes after ischemic insult. These data illuminate a previously unknown function for ALDH2 in cell survival decisions. Such mechanistic insights may spur the development of new diagnostic methods for and improved risk management of coronary artery disease, as well as genotype-specific cardiac therapies.

A. D. Ebert, K. Kodo, P. Liang, H. Wu, B. C. Huber, J. Riegler, J. Churko, J. Lee, P. de Almeida, F. Lan, S. Diecke, P. W. Burridge, J. D. Gold, D. Mochly-Rosen, J. C. Wu, 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. Sci. Transl. Med. 6, 255ra130 (2014). [PubMed]