Molecular Basis of Cardioprotection

Abstract

Abstract:Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/ reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.

Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways

“…The prosurvival kinases are activated in the first few minutes of reperfusion to attenuate reperfusion‐related cell injury by antiapoptotic mechanisms 46. The RISK pathway involves PI3K (phosphatidylinositol 3‐kinase)/AKT and ERK1/2,47 whereas the SAFE pathway involves NF‐κB and STAT3 48. The PI3K/AKT pathway has been shown to play a role in the antiapoptotic effects of gastrin 49.…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…In terms of cardiac protection via GPCR agonism/ischaemic preconditioning, ROS generation (via NADPH oxidase activity, mitochondrial electron transport chain) has been localised both up-and downstream of mitochondrial KATP channels and PKC (Hausenloy and Yellon, 2006;Murphy and Steenbergen, 2008;Heusch, 2015). However, ROS are also important in MMP activation and EGFR ligand shedding (Wetzker and Bohmer, 2003).…”

“…The enzyme is widely implicated in protective responses to preconditioning and GPCR stimuli (including PKC- - , and ), though some controversy remains regarding the involvement and protective functions of PKC (Hausenloy and Yellon, 2006). Within conventional protective signalling, PKC has been localised downstream of PI3K/Akt and NO/PKG and potentially both up-and downstream of mitochondrial KATP channels, with activation involving ROS generation (Hausenloy and Yellon, 2006;Murphy and Steenbergen, 2008;Heusch, 2015). Studies of preconditioning also localise PKC upstream of RTK activity (Baines et al, 1998), consistent with a role in regulating EGFR function and binding.…”

Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

“…However, STAT5 phosphorylation was associated with remote ischemic conditioning,21, 22 highlighting again species‐specific signaling differences. Independently of the involved myocardial signaling, mitochondria are viewed as end effectors of cardioprotective strategies 23, 24…”