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Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

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Abstract

Catestatin (CST) limits myocardial ischaemia/reperfusion (I/R) injury with unknown mechanisms. Clearly phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) isoforms, including intra-mitochondrial PKCε, mitochondrial KATP (mitoKATP) channels and subsequent reactive oxygen species (ROS)-signalling play important roles in postconditioning cardioprotection, preventing mitochondrial permeability transition pore (mPTP) opening. Therefore, we studied the role of these extra- and intra-mitochondrial factors in CST-induced protection. Isolated rat hearts and H9c2 cells underwent I/R and oxidative stress, respectively. In isolated hearts CST (75nM, CST-Post) given in early-reperfusion significantly reduced infarct size, limited post-ischaemic contracture, and improved recovery of developed left ventricular pressure. PI3K inhibitor, LY-294002 (LY), large spectrum PKC inhibitor, Chelerythrine (CHE), specific PKCε inhibitor (εV1-2), mitoKATP channel blocker, 5-Hydroxydecanoate (5HD) or ROS scavenger, 2-mercaptopropionylglycine (MPG) abolished the infarct-sparing effect of CST. Notably the CST-induced contracture limitation was maintained during co-infusion of 5HD, MPG or εV1-2, but it was lost during co-infusion of LY or CHE. In H9c2 cells challenged with H2O2, mitochondrial depolarization (an index of mPTP opening studied with JC1-probe) was drastically limited by CST (75nM). Our results suggest that the protective signalling pathway activated by CST includes mitoKATP channels, ROS signalling and prevention of mPTP opening, with a central role for upstream PI3K/Akt and PKCs. In fact, all inhibitors completely abolished CST-infarct-sparing effect. Since CST-anti-contracture effect cannot be explained by intra-mitochondrial mechanisms (PKCε activation and mitoKATP channel opening) or ROS signalling, it is proposed that these downstream signals are part of a reverberant loop which re-activates upstream PKCs, which therefore play a pivotal role in CST-induced protection.

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Acknowledgments

The authors wish to thank Prof. Donatella Gattullo for insightful suggestions, and Dr. Sushil K. Mahata for providing us with CST. This work was supported by National Institute for Cardiovascular Research (INRC-2010, to BT, GA, MCC, PP); Regione Piemonte (CP, GA, PP), ex-60 % (CP, PP, GA) and PRIN-2008 (BT, CP).

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None declared.

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Authors and Affiliations

  1. Department of Clinical and Biological Sciences, University of Torino, Orbassano, Turin, Italy

    Maria-Giulia Perrelli, Francesca Tullio, Carmelina Angotti, Claudia Penna & Pasquale Pagliaro

  2. Department of Life Sciences and Systems Biology, University of Torino, Turin, Italy

    Giuseppe Alloatti

  3. Department of Cell Biology, University of Calabria, Arcavacata di Rende, Cosenza, Italy

    Maria Carmela Cerra, Tommaso Angelone & Bruno Tota

  4. Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Cosenza, Italy

    Maria Carmela Cerra

  5. National Institute of Cardiovascular Research, Bologna, Italy

    Maria-Giulia Perrelli, Francesca Tullio, Maria Carmela Cerra, Tommaso Angelone, Bruno Tota, Giuseppe Alloatti, Claudia Penna & Pasquale Pagliaro

  6. Dipartimento di Scienze Cliniche e Biologiche, Facoltà di Medicina e Chirurgia “S. Luigi Gonzaga”, Regione Gonzole 10, 10043, Orbassano (TO), Italy

    Claudia Penna & Pasquale Pagliaro

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  1. Maria-Giulia Perrelli
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  2. Francesca Tullio
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  3. Carmelina Angotti
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Correspondence to Claudia Penna or Pasquale Pagliaro.

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Maria-Giulia Perrelli and Francesca Tullio contributed equally to this work

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Perrelli, MG., Tullio, F., Angotti, C. et al. Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling. Pflugers Arch - Eur J Physiol 465, 1031–1040 (2013). https://doi.org/10.1007/s00424-013-1217-0

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