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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

ALDH2 Activator Inhibits Increased Myocardial Infarction Injury by Nitroglycerin Tolerance

Full text
Author(s):
Sun, Lihan [1] ; Cesar, Julio [1] ; Ferreira, Batista [1] ; Mochly-Rosen, Daria [1]
Total Authors: 4
Affiliation:
[1] Stanford Univ, Dept Chem & Syst Biol, Sch Med, Stanford, CA 94305 - USA
Total Affiliations: 1
Document type: Journal article
Source: Science Translational Medicine; v. 3, n. 107 NOV 2 2011.
Web of Science Citations: 43
Abstract

Nitroglycerin, which treats impaired cardiac function through vasodilation as it is converted to nitric oxide, is used worldwide for patients with various ischemic and congestive cardiac diseases, including angina pectoris. Nevertheless, after continuous treatment, the benefits of nitroglycerin are limited by the development of tolerance to the drug. Nitroglycerin tolerance is a result of inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme essential for cardioprotection in animals subjected to myocardial infarction. Here, we tested the hypothesis that the tolerance that develops as a result of sustained nitroglycerin treatment increases cardiac injury by subsequent myocardial infarction. In a rat model of myocardial infarction, 16 hours of prior, sustained nitroglycerin treatment resulted in infarcts that were twice as large as those in untreated control animals and in diminished cardiac function at 3 days and 2 weeks after the myocardial infarction. We also sought to identify a potential treatment to protect against this increased cardiac damage. Nitroglycerin inhibited ALDH2 activity in vitro, an effect that was blocked by Alda-1, an activator of ALDH2. Co-administration of Alda-1 with the nitroglycerin prevented the nitroglycerin-induced increase in cardiac dysfunction after myocardial infarction in rats, at least in part by enhancing metabolism of reactive aldehyde adducts that impair normal protein functions. If our animal studies showing that nitroglycerin tolerance increases cardiac injury upon ischemic insult are corroborated in humans, activators of ALDH2 such as Alda-1 may help to protect patients with myocardial infarction from this nitroglycerin-induced increase in cardiac injury while maintaining the cardiac benefits of the increased nitric oxide concentrations produced by nitroglycerin. (AU)

FAPESP's process: 09/03143-1 - Protein quality control in heart failure: role of different protein kinase C isozymes
Grantee:Julio Cesar Batista Ferreira
Support Opportunities: Scholarships in Brazil - Post-Doctoral