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

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.
AuthorsMaria-Giulia Perrelli, Francesca Tullio, Carmelina Angotti, Maria Carmela Cerra, Tommaso Angelone, Bruno Tota, Giuseppe Alloatti, Claudia Penna, Pasquale Pagliaro
JournalPflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 465 Issue 7 Pg. 1031-40 (Jul 2013) ISSN: 1432-2013 [Electronic] Germany
PMID23319164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cardiotonic Agents
  • Chromogranin A
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Peptide Fragments
  • Phosphoinositide-3 Kinase Inhibitors
  • Potassium Channels
  • Reactive Oxygen Species
  • chromogranin A (344-364)
  • mitochondrial K(ATP) channel
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
Topics
  • Animals
  • Cardiotonic Agents (pharmacology, therapeutic use)
  • Cell Line
  • Chromogranin A (pharmacology, therapeutic use)
  • Male
  • Mitochondrial Membrane Transport Proteins (metabolism)
  • Mitochondrial Permeability Transition Pore
  • Myocardial Infarction (drug therapy)
  • Myocardial Reperfusion Injury (drug therapy, metabolism)
  • Oxidative Stress (drug effects)
  • Peptide Fragments (pharmacology, therapeutic use)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphoinositide-3 Kinase Inhibitors
  • Potassium Channels (metabolism)
  • Protein Kinase C (antagonists & inhibitors, metabolism)
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species (antagonists & inhibitors, metabolism)
  • Signal Transduction

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