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Urocortin-2 prevents dysregulation of Ca2+ homeostasis and improves early cardiac remodeling after ischemia and reperfusion

AuthorsDomínguez-Rodríguez, Alejandro; Mayoral-González, Isabel; Ávila-Medina, Javier; Rojas-de Pedro, Eva S. de; Calderón-Sánchez, Eva; Díaz Carrasco, Ignacio; Hmadcha, Abdelkrim ; Castellano, Antonio; Rosado, Juan A.; Benitah, Jean-Pierre; Gómez, Ana M. ; Ordóñez Fernández, Antonio ; Smani, Tarik
Ischemia and reperfusion
Adverse remodeling
Ca2+ dysregulation,
Store operated Ca2+ channels
Issue Date3-Jul-2018
PublisherFrontiers Media
CitationFrontiers in Physiology 9: 813 (2018)
Abstract[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.
Publisher version (URL)https://doi.org/10.3389/fphys.2018.00813
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