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Front Physiol. 2018 Jul 3;9:813. doi: 10.3389/fphys.2018.00813. eCollection 2018.

Urocortin-2 Prevents Dysregulation of Ca2+ Homeostasis and Improves Early Cardiac Remodeling After Ischemia and Reperfusion.

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Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CIBERCV, CSIC, Seville, Spain.
Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Seville, Spain.
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Junta de Andalucia, University of Pablo de Olavide, University of Seville, CSIC, Seville, Spain.
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain.
Departamento de Fisiología, Universidad de Extremadura, Cáceres, Spain.
UMR-S 1180, INSERM, Universite Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.


Aims: Urocortin-2 (Ucn-2) is a potent cardioprotector against Ischemia and Reperfusion (I/R) injuries. However, little is known about its role in the regulation of intracellular Ca2+ concentration ([Ca2+]i) under I/R. Here, we examined whether the addition of Ucn-2 in reperfusion promotes cardioprotection focusing on ([Ca2+]i handling. Methods and Results: Cardiac Wistar rat model of I/R was induced by transient ligation of the left coronary artery and experiments were conducted 1 week after surgery in tissue and adult cardiomyocytes isolated from risk and remote zones. We observed that I/R promoted significant alteration in cardiac contractility as well as an increase in hypertrophy and fibrosis in both zones. The study of confocal [Ca2+]i imaging in adult cardiomyocytes revealed that I/R decreased the amplitude of [Ca2+]i transient and cardiomyocytes contraction in risk and remote zones. Interestingly, intravenous infusion of Ucn-2 before heart's reperfusion recovered significantly cardiac contractility and prevented fibrosis, but it didn't affect cardiac hypertrophy. Moreover, Ucn-2 recovered the amplitude of [Ca2+]i transient and modulated the expression of several proteins related to [Ca2+]i homeostasis, such as TRPC5 and Orai1 channels. Using Neonatal Rat Ventricular Myocytes (NRVM) we demonstrated that Ucn-2 blunted I/R-induced Store Operated Ca2+ Entry (SOCE), decreased the expression of TRPC5 and Orai1 as well as their interaction in reperfusion. Conclusion: Our study provides the first evidences demonstrating that Ucn-2 addition at the onset of reperfusion attenuates I/R-induced adverse cardiac remodeling, involving the [Ca2+]i handling and inhibiting the expression and interaction between TRPC5 and Orai1.


Ca2+ dysregulation; Urocortin-2; adverse remodeling; ischemia and reperfusion; store operated Ca2+ channels

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