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Mitochondria to nucleus translocation of AIF in mice lacking Hsp70 during ischemia/reperfusion

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Abstract

Heat shock protein 70 (Hsp70) has been shown to have an anti-apoptotic function, but its mechanism is not clear in heart. In this study, we examined the effect of Hsp70 deletion on AIF-induced apoptosis during ischemia/reperfusion (I/R) in vivo. Although Hsp70 KO and WT mice demonstrated similar amounts of AIF released from mitochondria after I/R surgery, Hsp70 KO mice showed a significantly greater increase in apoptosis, larger infarct size, and decreased cardiac output. There was also a significant fourfold increase in the nuclear accumulation of AIF in Hsp70 KO mice compared with WT mice. Treatment with 4-AN (4-amino-1,8-napthalimide, 3 mg/kg), a potent inhibitor of PARP-1, which is a critical regulator of AIF-induced apoptosis, significantly blocked the release of AIF from mitochondria and the translocation of AIF into the nuclei after I/R in both WT and Hsp70 KO mice. In addition, 4-AN treatment resulted in a significant inhibition of apoptosis, a reduction of infarct size, and attenuated cardiac dysfunction in both WT and Hsp70 KO mice after I/R. The anti-apoptotic function of Hsp70 occurs through the inhibition of AIF-induced apoptosis by blocking the mitochondria to nucleus translocation of AIF. PARP-1 inhibition improves cardiac function by blocking AIF-induced apoptosis.

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Acknowledgments

This study was supported by the grants from National Institutes of Health RO1 HL091998 (PMK) and the World Class University program (R31-20029) from Ministry of Education, Science and Technology, South Korea (PMK).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Sangita Choudhury, Soochan Bae, Qingen Ke, Ji Yoo Lee, Jacob Kim & Peter M. Kang

  2. Department of BIN Fusion Technology, Chonbuk National University, Jeonju, South Korea

    Peter M. Kang

  3. Cardiovascular Institute, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, CLS-910, Boston, MA, 02215, USA

    Peter M. Kang

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  1. Sangita Choudhury
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Correspondence to Peter M. Kang.

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Choudhury, S., Bae, S., Ke, Q. et al. Mitochondria to nucleus translocation of AIF in mice lacking Hsp70 during ischemia/reperfusion. Basic Res Cardiol 106, 397–407 (2011). https://doi.org/10.1007/s00395-011-0164-1

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