Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore.

Reperfusion injury is responsible for an important part of myocardial infarct establishment due notably to triggering cardiomyocytes death at the first minutes of reperfusion. AZP-531 is an optimized analog of unacylated ghrelin currently in clinical development in several metabolic diseases. We investigated a potential cardioprotective effect of AZP-531 in ischemia/reperfusion (IR) and the molecular underlying mechanism(s) involved in this protection. In vivo postconditioning with AZP-531 in C57BL6 mouse IR model decreased infarct size. Western blot analysis on areas at risk from the different mouse groups showed that AZP-531 activates Akt, ERK1-2 as well as S6 and 4EBP1, mTORC1 effectors. We also showed an inhibition of caspase 3 cleavage and Bax translocation to the mitochondria. AZP-531 also stimulated the expression of antioxidants and was capable of decreasing mitochondrial H2O2 production, contributing to the reduction of ROS accumulation. AZP-531 exhibits cardioprotective effect when administrated for postconditioning in C57BL6 mouse IR model. Treatment with AZP-531 rescued the myocardium from cell death at early reperfusion by stimulating protein synthesis, inhibiting Bax/caspase 3-induced apoptosis as well as ROS accumulation and oxidative stress-induced necrosis. AZP-531 may prove useful in the treatment of IR injury.