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1 Boston Biomedical Research Institute, Watertown, MA, USA
2 Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA
3 Department of Medicine, Caritas St. Elizabeth's Medical Center, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: erhardt{at}bbri.org.
Puma, a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and independent forms of apoptosis and has been implicated in the pathomechanism of several diseases including cancer, AIDS and ischemic brain disease. The role of Puma in cardiac myocyte death, however, has not yet been analyzed. Based on the ability of Puma to integrate diverse cell death stimuli, we hypothesized that Puma might be critical for cardiomyocyte death upon ischemia/reperfusion of the heart. Here we show that hypoxia/reoxygenation of isolated cardiomyocytes led to an increase in Puma mRNA and protein levels. Moreover, if Puma was delivered by an adenoviral construct, cardiac myocytes died by apoptosis. Under ATP-depleted conditions, however, Puma overexpression primarily induced necrosis, suggesting that Puma is involved in the development of both types of cell death. Consistent with these findings, targeted deletion of Puma in a mouse model attenuated both apoptosis and necrosis. Compared to wild-type mice, Puma-/- mice exhibited infarcts that were approximately 50% smaller, using the Langendorff ex vivo ischemia/reperfusion model. As a result, following ischemia/reperfusion Puma-/- hearts preserved cardiac function significantly better than their wild-type littermates. Our study thus establishes Puma as an essential mediator of cardiac myocyte death upon ischemia/reperfusion injury and offers a novel therapeutic target to limit cell loss in ischemic heart disease.
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