1. Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling
- Author
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Francesca Tullio, Bruno Tota, Tommaso Angelone, Giuseppe Alloatti, Carmelina Angotti, Maria-Giulia Perrelli, Pasquale Pagliaro, Maria Carmela Cerra, and Claudia Penna
- Subjects
Male ,Cardiotonic Agents ,Potassium Channels ,Physiology ,Clinical Biochemistry ,Myocardial Infarction ,Myocardial Reperfusion Injury ,Mitochondrial Membrane Transport Proteins ,Cell Line ,chemistry.chemical_compound ,Phosphatidylinositol 3-Kinases ,Physiology (medical) ,medicine ,Catestatin Chromogranin A Cardioprotection Ischaemia/reperfusion Postconditioning ,Animals ,Rats, Wistar ,Protein kinase B ,Protein kinase C ,PI3K/AKT/mTOR pathway ,Protein Kinase C ,Phosphoinositide-3 Kinase Inhibitors ,Cardioprotection ,business.industry ,Mitochondrial Permeability Transition Pore ,MPTP ,medicine.disease ,Peptide Fragments ,Cell biology ,Rats ,Oxidative Stress ,Chelerythrine ,chemistry ,Mitochondrial permeability transition pore ,Anesthesia ,Chromogranin A ,business ,Reactive Oxygen Species ,human activities ,Reperfusion injury ,Proto-Oncogene Proteins c-akt ,Signal Transduction - 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 PKCe, 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 PKCe inhibitor (eV1-2), 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 eV1-2, 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 (PKCe 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.
- Published
- 2012