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J. Biol. Chem., Vol. 281, Issue 40, 29776-29787, October 6, 2006

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Enhancing Macroautophagy Protects against Ischemia/Reperfusion Injury in Cardiac Myocytes^*

From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

Cardiac myocytes undergo programmed cell death as a result of ischemia/reperfusion (I/R). One feature of I/R injury is the increased presence of autophagosomes. However, to date it is not known whether macroautophagy functions as a protective pathway, contributes to programmed cell death, or is an irrelevant event during cardiac I/R injury. We employed simulated I/R of cardiac HL-1 cells as an in vitro model of I/R injury to the heart. To assess macroautophagy, we quantified autophagosome generation and degradation (autophagic flux), as determined by steady-state levels of autophagosomes in relation to lysosomal inhibitor-mediated accumulation of autophagosomes. We found that I/R impaired both formation and downstream lysosomal degradation of autophagosomes. Overexpression of Beclin1 enhanced autophagic flux following I/R and significantly reduced activation of pro-apoptotic Bax, whereas RNA interference knockdown of Beclin1 increased Bax activation. Bcl-2 and Bcl-x_L were protective against I/R injury, and expression of a Beclin1 Bcl-2/-x_L binding domain mutant resulted in decreased autophagic flux and did not protect against I/R injury. Overexpression of Atg5, a component of the autophagosomal machinery downstream of Beclin1, did not affect cellular injury, whereas expression of a dominant negative mutant of Atg5 increased cellular injury. These results demonstrate that autophagic flux is impaired at the level of both induction and degradation and that enhancing autophagy constitutes a powerful and previously uncharacterized protective mechanism against I/R injury to the heart cell.

Received for publication, April 20, 2006 , and in revised form, June 23, 2006.

^* This work was supported by National Institutes of Health Grants RO1-AJ21568 and RO1-HL60590 (to R. A. G.) and the Stein Endowment Fund. This is manuscript number 17717-MEM of The Scripps Research Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular and Experimental Medicine MEM-220, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-9165; Fax: 858-784-8389; E-mail: robbieg{at}scripps.edu.

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