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Oleylethanolamide Activates Ras-Erk Pathway and Improves Myocardial Function in Doxorubicin-Induced Heart Failure

Department of Medicine, Biological Chemistry, Physiology, and Biophysics (H.-F.S., A.S., Y.-X.S., Y.-H.C., P.H.W.), Center for Cardiovascular Hormone Research, and Department of Psychiatry (J.F., D.P.), University of California, Irvine, California 92697

Address all correspondence and requests for reprints to: Ping H. Wang, M.D., Department of Medicine, Med Sci 1, C240, Irvine, California 92697. E-mail: phwang{at}uci.edu.

Oleylethanolamide (OEA) is a natural fatty acid ethanolamide produced in the heart, but its biological actions in myocardium have not yet been defined. This study was carried out to determine whether OEA could be used to prevent the development of heart failure or improve evolving heart failure. We studied in vivo and in vitro actions of OEA in cardiac muscle. In an animal model of doxorubicin cardiomyopathy, OEA showed robust effects and attenuated the progression of systolic/diastolic dysfunction and ventricular remodeling. During evolving doxorubicin cardiomyopathy, a therapeutic course of OEA treatment partially restored myocardial function. The preventive and therapeutic effects of OEA were associated with significant improvement of survival. To investigate the mechanism of OEA action in cardiac muscle, we have carried out in vitro experiments in cultured cardiomyocytes. The results showed that OEA, through activation of Ras-Raf-1-Mek-Erk signaling, inhibited doxorubicin-induced apoptosis. Additional experiments showed that OEA activation of the Erk pathway involved activation of Neu/ErbB2 receptor, which suggests OEA actions in cardiac muscle might require activation of Neu/ErbB2. In summary, OEA improved ventricular remodeling and augmented cardiac function in doxorubicin cardiomyopathy, possibly involving activation of Neu/ErbB2 and Ras-Erk signaling. These findings suggest OEA is a novel cardioprotective compound that may be used to develop new strategies for the management of cardiomyopathy.

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