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

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

doi:10.1371/journal.pone.0147375

Cited by 24 publications

(24 citation statements)

References 43 publications

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“…However, a recent study demonstrated that both Epac isoforms are present within mitochondria isolated from adult rat myocytes (Wang et al, 2016). Current findings using rat hearts have implied that the cardioprotective effect induced by urocortin‐1 is mediated by activation of Epac2 (Calderon‐Sanchez et al, 2016) and that Epac2 inhibition promotes cardiac arrhythmias (Yang et al, 2016). Nonetheless, in the absence of direct evidence, a role for the Epac1 isoform cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Khaliulin

Bond

James

et al. 2017

British J Pharmacology

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Background and PurposeMyocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R.Experimental ApproachHearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca2+ transients.Key ResultsSelective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCε activation and repressed by inhibitors of PKA, Epac or PKC.Conclusion and ImplicationsSimultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCε activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults.

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Section: Discussionmentioning

confidence: 99%

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Khaliulin

Bond

James

et al. 2017

British J Pharmacology

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“…"Clearly, the development of the first antagonists with (subtype) selectivity for EPAC represents another research milestone to ascribe biologic responses to EPAC" (915). Indeed, these selective EPAC2 inhibitors are becoming effective tools in probing isoform-specific EPAC functions (18,47,130,175,226,250,302,411,463,565,682,743,841,896,961,1114).…”

Section: B Epac Specific Antagonistsmentioning

confidence: 99%

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

Robichaux

Cheng

2018

Physiological Reviews

160

226

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This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses. This review comprehensively covers EPAC protein functions at the molecular, cellular, physiological, and pathophysiological levels; and in turn, the applications of employing EPAC-based biosensors as detection tools for dissecting cAMP signaling and the implications for targeting EPAC proteins for therapeutic development are also discussed.

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“…38 Interestingly, it is reported that Urocortin-1 prevented the heart from ischemia and reperfusion injury by increasing cell survival and stimulating the apoptosis-related genes CD40lg, XIAP, and BAD. 39 Recently, studies have shown that the interaction of miRNAs and their target genes can affect the progression of human diseases. For example, miR-146a prohibits against myocardial ischaemia reperfusion injury via targeting Med1.…”

Section: Discussionmentioning

confidence: 99%

LncRNA KCNQ1OT1 attenuates sepsis-induced myocardial injury via regulating miR-192-5p/XIAP axis

Sun

Yuan

et al. 2020

Exp Biol Med (Maywood)

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Myocardial dysfunction is a prime cause of death in sepsis. This study is to delve into the function of lncRNA KCNQ1OT1 in myocardial injury induced by sepsis. Sepsis-induced myocardial injury model in rat was initiated by intraperitoneally injecting of LPS (10 mg/kg) in vivo, and cardiomyocyte H9c2 was treated with LPS to mimic sepsis in vitro. KCNQ1OT1 and miR-192-5p expressions were detected by qRT-PCR. The cell viability was probed with CCK-8 experiment and the apoptosis of the cardiomyocytes was tested using flow cytometry analysis. Western blot was operated to determine apoptosis-related proteins expressions. ELISA was used to evaluate the levels of TNF-α, IL-6, and IL-1β. Bioinformatics analysis, RT-PCR, dual luciferase reporter assay, and RNA immunoprecipitation experiment were utilized to detect the interrelation of genes. Herein, we proved that KCNQ1OT1 was considerably down-regulated, whereas miR-192-5p was markedly increased in myocardial tissues of septic rats. KCNQ1OT1 interrelated with miR-192-5p, and negatively modulated its expression levels. Overexpression of KCNQ1OT1 or the transfection of miR-192-5p inhibitors greatly facilitated the viability and impeded the apoptosis of H9c2 cardiomyocytes. miR-192-5p paired with the 3ʹUTR of XIAP, and repressed its protein expression, and XIAP was modulated positively by KCNQ1OT1. In conclusion, our work indicates that down-regulation of KCNQ1OT1 advances cardiac injury through regulating miR-192-5p/XIAP axis during sepsis. Impact statement Sepsis-induced cardiomyopathy remains to be a major challenge to health care systems around the globe. There are no known therapies currently available that can cure the disease. This study provides convincing evidence that KCNQ1OT1 could attenuate sepsis-mediated myocardial injury. We further demonstrate that the beneficial function of KCNQ1OT1 was achieved by regulating the miR-192-5p/XIAP axis. We therefore found a new mechanism of cardioprotective effect of KCNQ1OT1, one which also offers a novel theoretical basis for the therapy of sepsis-induced cardiomyopathy.

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

Cited by 24 publications

References 43 publications

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

LncRNA KCNQ1OT1 attenuates sepsis-induced myocardial injury via regulating miR-192-5p/XIAP axis

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