Urocortin-1 Mediated Cardioprotection Involves XIAP and CD40-Ligand Recovery: Role of EPAC2 and ERK1/2.

Eva Calderón-Sánchez,Tarik Smani,Antonio Ordóñez,Ignacio Díaz

doi:10.1371/journal.pone.0147375

Eva Calderón-Sánchez, Tarik Smani + Show 2 more

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https://doi.org/10.1371/journal.pone.0147375

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Abstract

AimsUrocortin-1 (Ucn-1) is an endogenous peptide that protects heart from ischemia and reperfusion (I/R) injuries. Ucn-1 is known to prevent cardiac cell death, but its role in the transcription of specific genes related to survival signaling pathway has not been fully defined. The aim of this study was to investigate the molecular signaling implicated in the improvement of cardiac myocytes survival induced by Ucn-1.Methods and ResultsUcn-1 administration before ischemia and at the onset of reperfusion, in rat hearts perfused in Langendorff system, fully recovered heart contractility and other hemodynamic parameters. Ucn-1 enhanced cell viability and decreased lactate dehydrogenase (LDH) release in adult cardiac myocytes subjected to simulated I/R. Annexin V-FITC/PI staining indicated that Ucn-1 promoted cell survival and decreased cell necrosis through Epac2 (exchange protein directly activated by cAMP) and ERK1/2 (extracellular signal–regulated kinases 1/2) activation. We determined that Ucn-1 shifted cell death from necrosis to apoptosis and activated caspases 9 and 3/7. Furthermore, mini-array, RT-qPCR and protein analyses of apoptotic genes showed that Ucn-1 upregulated the expression of CD40lg, Xiap and BAD in cells undergoing I/R, involving Epac2 and ERK1/2 activation.ConclusionsOur data indicate that Ucn-1 efficiently protected hearts from I/R damage by increasing the cell survival and stimulated apoptotic genes, CD40lg, Xiap and BAD, overexpression through the activation of Epac2 and ERK1/2.

Highlights

Despite the considerable advances that have been made in the field of myocardial protection, ischemic heart disease represents a major public health problem and the main cause of mortality in the industrialized world [1]
Annexin V-FITC/propidium iodide (PI) staining indicated that Ucn-1 promoted cell survival and decreased cell necrosis through Epac2 and ERK1/2 activation
Mini-array, RT-qPCR and protein analyses of apoptotic genes showed that Ucn-1 upregulated the expression of CD40 ligand (CD40lg), Xiap and Bcl-2associated death promoter (BAD) in cells undergoing ischemia and reperfusion (I/R), involving Epac2 and ERK1/2 activation

Summary

Introduction

Despite the considerable advances that have been made in the field of myocardial protection, ischemic heart disease represents a major public health problem and the main cause of mortality in the industrialized world [1]. Percutaneous transluminal angioplasty, fibrinolysis and cardioplegic solutions are some of the strategies developed to preserve the myocardial viability from ischemia. All these procedures involve myocardial reperfusion/reoxygenation after an ischemic episode. In the last two-decade, urocortin peptides (Ucn-1, Ucn-2, Ucn-3), which belongs to the corticotropin-releasing factor (CRF) family [3], have emerged as a potential therapeutic agonist that improves heart performances and protects heart from I/R injuries [4]. We have described that Epac and ERK1/2 are involved in urocortin-induced positive inotropism in rat hearts [9].

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