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

  • Maria-Giulia Perrelli
  • Francesca Tullio
  • Carmelina Angotti
  • Maria Carmela Cerra
  • Tommaso Angelone
  • Bruno Tota
  • Giuseppe Alloatti
  • Claudia PennaEmail author
  • Pasquale PagliaroEmail author
Organ Physiology

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.

Keywords

Catestatin Chromogranin A Cardioprotection Ischaemia/reperfusion Postconditioning 

Notes

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).

Conflict of interest

None declared.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Maria-Giulia Perrelli
    • 1
    • 5
  • Francesca Tullio
    • 1
    • 5
  • Carmelina Angotti
    • 1
  • Maria Carmela Cerra
    • 3
    • 4
    • 5
  • Tommaso Angelone
    • 3
    • 5
  • Bruno Tota
    • 3
    • 5
  • Giuseppe Alloatti
    • 2
    • 5
  • Claudia Penna
    • 1
    • 5
    • 6
    Email author
  • Pasquale Pagliaro
    • 1
    • 5
    • 6
    Email author
  1. 1.Department of Clinical and Biological SciencesUniversity of TorinoTurinItaly
  2. 2.Department of Life Sciences and Systems BiologyUniversity of TorinoTurinItaly
  3. 3.Department of Cell BiologyUniversity of CalabriaCosenzaItaly
  4. 4.Department of Pharmaco-BiologyUniversity of CalabriaCosenzaItaly
  5. 5.National Institute of Cardiovascular ResearchBolognaItaly
  6. 6.Dipartimento di Scienze Cliniche e BiologicheFacoltà di Medicina e Chirurgia “S. Luigi Gonzaga”Orbassano (TO)Italy

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