Background: CST exerts anti-hypertensive, vasodilator and cardiac inotropic effects acting via nitric-oxide signaling. We tested whether CST cardioprotection activates RISK pathway and a reactive oxygen species (ROS) signaling. Methods: Isolated rat hearts underwent 30-min ischemia and 120-min reperfusion (I/R) without or with CST (75 nM, CST-Post) given for 20-min in early reperfusion. To evaluate the role of PKC and mitochondrial KATP (mitoKATP) channels, hearts were co-infused with CST, and either the PKC inhibitor (chelerythrine) or the mitoKATP channel blocker (5-hydroxy-decanoate). We tested the phosphorylation (PP) of RISK elements (Akt, PKCε and GSK3β) and the levels of anti-apoptotic marker (Bcl-2). Coronary pressure and left ventricular pressure (LVP) were monitored. Infarct size (IS) was evaluated with NBT-staining. Results: IS was 67±6% of risk area in hearts subjected to I/R only. CST-Post reduced IS to 37±4%, and improved postischemic contracture and recovery of developed LVP. CST-Post induced PP of all tested RISK elements and preserved Bcl-2 levels. The PKC inhibitor chelerythrine abolished CST protection and allowed a partial PP of Akt only. Blockade of mitoKATP channels abolished the IS limitation and GSK3β-PP, but allowed contracture limitation and partial PP of Akt and PKCε. Also 2- mercaptopropionylglycine (MPG) abolished the infarct-sparing effect of CST. Conclusions: Results suggest that CST-Post cardioprotection against IS and postischemic contractile dysfunction depends on Akt and PKCε PP/ activation and on PP/inhibition of GSK3β via a redox-sensible mechanism. We propose a reverberant circuit from Akt to PKCε and to mitoKATP channels and again to PKCε and to GSK3β via the ROS signaling.
Postconditioning (PostC) cardioprotection by chromogranin A (CgA)-derived catestatin (CTS) in isolated rat hearts is mediated by RISK (Reperfusion Injury Salvage Kinases) pathway and redox-mechanisms
ANGOTTI, CARMELINA;PENNA, Claudia;PERRELLI, MARIA-GIULIA;PAGLIARO, Pasquale
2012-01-01
Abstract
Background: CST exerts anti-hypertensive, vasodilator and cardiac inotropic effects acting via nitric-oxide signaling. We tested whether CST cardioprotection activates RISK pathway and a reactive oxygen species (ROS) signaling. Methods: Isolated rat hearts underwent 30-min ischemia and 120-min reperfusion (I/R) without or with CST (75 nM, CST-Post) given for 20-min in early reperfusion. To evaluate the role of PKC and mitochondrial KATP (mitoKATP) channels, hearts were co-infused with CST, and either the PKC inhibitor (chelerythrine) or the mitoKATP channel blocker (5-hydroxy-decanoate). We tested the phosphorylation (PP) of RISK elements (Akt, PKCε and GSK3β) and the levels of anti-apoptotic marker (Bcl-2). Coronary pressure and left ventricular pressure (LVP) were monitored. Infarct size (IS) was evaluated with NBT-staining. Results: IS was 67±6% of risk area in hearts subjected to I/R only. CST-Post reduced IS to 37±4%, and improved postischemic contracture and recovery of developed LVP. CST-Post induced PP of all tested RISK elements and preserved Bcl-2 levels. The PKC inhibitor chelerythrine abolished CST protection and allowed a partial PP of Akt only. Blockade of mitoKATP channels abolished the IS limitation and GSK3β-PP, but allowed contracture limitation and partial PP of Akt and PKCε. Also 2- mercaptopropionylglycine (MPG) abolished the infarct-sparing effect of CST. Conclusions: Results suggest that CST-Post cardioprotection against IS and postischemic contractile dysfunction depends on Akt and PKCε PP/ activation and on PP/inhibition of GSK3β via a redox-sensible mechanism. We propose a reverberant circuit from Akt to PKCε and to mitoKATP channels and again to PKCε and to GSK3β via the ROS signaling.
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