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Diazoxide postconditioning induces mitochondrial protein S-Nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE

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Abstract

Postconditioning (PostC) can be obtained either with brief cycles of ischemia/reperfusion (I-PostC) or with a direct targeting of mitochondria with Diazoxide (pharmacological PostC, P-PostC). I-PostC may induce the activation of RISK and SAFE pathways and may favor nitric oxide production with S-Nitrosylation of proteins and redox signaling. It is not clear whether Diazoxide can lead to similar effects. We compared the effects of I-PostC and P-PostC on (a) kinases of RISK- and SAFE pathway, (b) S-Nitrosylation of mitochondrial proteins and (c) reduction of death signals (PKCδ, cleaved caspase-3 and Beclin-1) in cytosolic and mitochondrial fractions. Isolated rat hearts underwent (1) perfusion without ischemia (Sham), (2) ischemia/reperfusion (30-min ischemia plus 2-h reperfusion), (3) I-PostC (5 intermittent cycles of 10-s reperfusion and 10-s ischemia immediately after the 30-min ischemia), (4) P-PostC (Diazoxide 30 μM in the first of 3-min of reperfusion) or (5) I-PostC + MPG or P-PostC + MPG (MPG, 2-mercaptopropionylglycine 300 μM). Using Western blot and biotin switch assay, we found that P-PostC induced a redox sensible phosphorylation/translocation of Akt, ERK1/2 and GSK3β into the mitochondria, but not of phospho-STAT3, which was translocated into the mitochondria by I-PostC only. Either I-PostC or P-PostC increased mitochondrial S-Nitrosylated proteins (e.g., VDAC) and reduced the levels of phospho-PKCδ, cleaved caspase-3 and Beclin-1. Therefore, direct targeting of mitochondria with Diazoxide (a) activates the RISK pathway via a redox signaling, (b) favors discrete mitochondrial protein S-Nitrosylation, including VDAC and (c) decreases signals of death. Intriguingly, phospho-STAT3 translocation is induced by I-PostC, but not by P-PostC, thus suggesting a redox-independent mechanism in the SAFE pathway.

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Acknowledgments

The authors wish to thank Prof. Donatella Gattullo for insightful suggestions and Sara Femminò for technical assistance. This work was supported by National Institutes of Cardiovascular Research (INRC-2010, to PP); Regione Piemonte (CP, PP), ex-60 % (CP, PP), PRIN-2008 (CP) and AIRC IG 13009 (VP).

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None declared.

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Authors and Affiliations

  1. Dipartimento di Scienze Cliniche e Biologiche, Facoltà di Medicina e Chirurgia “S. Luigi Gonzaga”, Università di Torino, Regione Gonzole 10, 10043, Orbassano, TO, Italy

    C. Penna, M.-G. Perrelli, F. Tullio, C. Angotti & P. Pagliaro

  2. Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università di Torino, Torino, Italy

    A. Camporeale & V. Poli

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  1. C. Penna
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  2. M.-G. Perrelli
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  3. F. Tullio
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  5. A. Camporeale
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  7. P. Pagliaro
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Correspondence to P. Pagliaro.

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C. Penna, M.-G. Perrelli contributed equally to this work.

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Penna, C., Perrelli, MG., Tullio, F. et al. Diazoxide postconditioning induces mitochondrial protein S-Nitrosylation and a redox-sensitive mitochondrial phosphorylation/translocation of RISK elements: no role for SAFE. Basic Res Cardiol 108, 371 (2013). https://doi.org/10.1007/s00395-013-0371-z

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  • DOI: https://doi.org/10.1007/s00395-013-0371-z

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