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

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.

TRPC channels: Dysregulation and Ca²⁺ Mishandling In Ischemic Heart Disease

“…Since it is known that the activation of TRPC channels mediates the Ca 2+ influx which in post-MI heart damages. Cardiac hypertrophy is also observed in rat heart tissue as early as 1 week post-I/R, which correlates with the upregulation of the expression of TRPC1, 3, 4, 5 and 6 mRNA [13] and the activation of the so-called fetal gene program, the markers of cardiac hypertrophy (unpublished data). Recently, Dragún et al [104] [13].…”

“…In human cardiac tissues and/or neonatal rat cardiomyocytes mRNA of TRPC5 [20,21] and TRPC6 [22] were detected. In animal model, the expression of TRPC1/3-7 have been confirmed in adult rat and mouse ventricle and atrial cardiac myocytes either at mRNA or protein levels [13,23,24]. Others reports showed that TRPC1/3-6 are expressed in rat ventricular myocytes of fetal and neonatal ventricular myocytes [19,25].…”

“…Although, the induced stress-stimulated contractility, known as the Anrep effect, is diminished in isolated papillary muscles and cardiomyocytes from TRPC6 KO, but not TRPC3 KO mice [59]. In [13,19,27,34,61]. Here, we will discuss the role of TRPC channels in processes related to cardiac ischemic diseases.…”

“…The activation of different isoform of TRP has been associated with cell-membrane depolarization, for example in smooth muscle cells (for review [6][7][8]) and in cardiac cells [9][10][11]. There are substantial evidences that TRP channels have important roles in mediating cardiac pathological processes, including cardiac hypertrophy and fibrosis [4,[12][13][14],which all lead to deleterious cardiac remodeling and subsequent heart failure (HF). This review focusses on the role of TRPC channels and provides an overview of the most relevant and recent findings related to this channels and ischemia related disease in the heart.…”

Specific Upregulation of TRPC1 and TRPC5 Channels by Mineralocorticoid Pathway in Adult Rat Ventricular Cardiomyocytes

“…Notably, TRPC1 channels are believed to mediate the non-selective cation current and to form SOC channels as a component in human atria [63], in the mouse sinoatrial node [64], in human cardiac c-kit+ progenitor cells [65], in NRVMs [66], and in adult ventricular cardiomyocytes [36,46,67]. Similarly, TRPC5, which was found to contribute to the formation of SOCE in smooth muscle cells isolated from rabbit pial arterioles [68], contributes to SOCE in NRVMs [11,69]. In addition, STIM1, the critical constituent of SOCE, can directly bind to and activate TRPC1 and TRPC5 channels via interactions in its ezrin/radixin/moesin (ERM) domain [70][71][72][73][74][75][76].…”