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

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          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 Ca 2+ concentration ([Ca 2+] i) under I/R. Here, we examined whether the addition of Ucn-2 in reperfusion promotes cardioprotection focusing on ([Ca 2+] 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 [Ca 2+] i imaging in adult cardiomyocytes revealed that I/R decreased the amplitude of [Ca 2+] 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 [Ca 2+] i transient and modulated the expression of several proteins related to [Ca 2+] 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 Ca 2+ 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 [Ca 2+] i handling and inhibiting the expression and interaction between TRPC5 and Orai1.

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          Most cited references 40

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          Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.

          Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.
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            Characterizing proteins and their interactions in cells and tissues using the in situ proximity ligation assay.

            The activity of proteins is typically regulated by secondary modifications and by interactions with other partners, resulting in the formation of protein complexes whose functions depend on the participating proteins. Accordingly, it is of central importance to monitor the presence of interaction complexes as well as their localization, thus providing information about the types of cells where the proteins are located and in what sub-cellular compartment these interactions occur. Several methods for visualizing protein interactions in situ have been developed during the last decade. These methods in most cases involve genetic constructs, and they have been successfully used in assays of living cell maintained in tissue culture, but they cannot easily be implemented in studies of clinical specimens. For such samples, affinity reagents like antibodies can be used to target the interacting proteins. In this review we will describe the in situ proximity ligation assays (in situ PLA), a method that is suitable for visualizing protein interactions in both tissue sections and in vitro cell lines, and we discuss research tasks when this or other method may be selected.
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              Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure.

              Cardiac hypertrophy and heart failure caused by high blood pressure were studied in single myocytes taken from hypertensive rats (Dahl SS/Jr) and SH-HF rats in heart failure. Confocal microscopy and patch-clamp methods were used to examine excitation-contraction (EC) coupling, and the relation between the plasma membrane calcium current (ICa) and evoked calcium release from the sarcoplasmic reticulum (SR), which was visualized as "calcium sparks." The ability of ICa to trigger calcium release from the SR in both hypertrophied and failing hearts was reduced. Because ICa density and SR calcium-release channels were normal, the defect appears to reside in a change in the relation between SR calcium-release channels and sarcolemmal calcium channels. beta-Adrenergic stimulation largely overcame the defect in hypertrophic but not failing heart cells. Thus, the same defect in EC coupling that develops during hypertrophy may contribute to heart failure when compensatory mechanisms fail.

                Author and article information

                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                03 July 2018
                : 9
                1Cardiovascular Pathophysiology, Institute of Biomedicine of Seville, University Hospital of Virgen del Rocío, University of Seville, CIBERCV, CSIC , Seville, Spain
                2Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla , Seville, Spain
                3Department 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
                4Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas , Madrid, Spain
                5Departamento de Fisiología, Universidad de Extremadura , Cáceres, Spain
                6UMR-S 1180, INSERM, Universite Paris-Sud, Université Paris-Saclay , Châtenay-Malabry, France
                Author notes

                Edited by: Fabio Mammano, Istituto di Biologia Cellulare e Neurobiologia (IBCN), Italy

                Reviewed by: Takahito Miyake, University of California, San Francisco, United States; Gourav Roy Choudhury, Texas Biomedical Research Institute, United States

                *Correspondence: Alejandro Domínguez-Rodríguez, adominguez-ibis@ 123456us.es Tarik Smani, tasmani@ 123456us.es

                These authors have contributed equally to this work.

                This article was submitted to Membrane Physiology and Membrane Biophysics, a section of the journal Frontiers in Physiology

                Copyright © 2018 Domínguez-Rodríguez, Mayoral-Gonzalez, Avila-Medina, de Rojas-de Pedro, Calderón-Sánchez, Díaz, Hmadcha, Castellano, Rosado, Benitah, Gomez, Ordoñez and Smani.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 8, Tables: 2, Equations: 0, References: 45, Pages: 16, Words: 0
                Original Research


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