Epac activation inhibits IL-6-induced cardiac myocyte dysfunction

Jin, Huiling; Fujita, Takayuki; Jin, Meihua; Kurotani, Reiko; Hidaka, Yuko; Cai, Wenqian; Suyama, Kenji; Prajapati, Rajesh; Chen, Liang; Okita, Yoshiki; Mototani, Yasumasa; Umemura, Masanari; Yokoyama, Utako; Sato, Motohiko; Okumura, Satoshi; Ishikawa, Yoshihiro

doi:10.1007/s12576-016-0509-5

Cited by 17 publications

(17 citation statements)

References 43 publications

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“…Recently, several reports have identified the roles of Epac in the development of cardiac diseases including arrhythmias. 10,11,[13][14][15][16][17] These findings indicate that inhibition of Epac function may be a novel and useful strategy for the treatment of arrhythmias. However, there have been no reports on the antiarrhythmic effects or cardiac side-effects of Epac inhibitors in vivo.…”

mentioning

confidence: 93%

Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice

Prajapati

Fujita

Suyama

et al. 2019

Circ J

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Background: It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of β-adrenergic receptor (β-AR), may be an effective target for the treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo. Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca 2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca 2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca 2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. Conclusions: These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice.

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confidence: 93%

Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice

Prajapati

Fujita

Suyama

et al. 2019

Circ J

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“…For example, activation of EPAC1 leads to SOCS3 induction, blockade of IL6 JAK/STAT3 signalling and potentiation of barrier function in vitro and in vivo, in normal mice [ 36 ]. Moreover, activation of EPAC in cardiac myocytes attenuates the inhibitory effect of IL6 on cardiac function and contractility in response to isoproterenol, most likely through inhibition of the JAK/STAT3 signalling by SOCS3 [ 37 ]. Using high throughput screening (HTS) we identified a novel ligand (I942) that exhibits agonist properties against EPAC1, but not EPAC2.…”

Section: Introductionmentioning

confidence: 99%

The novel exchange protein activated by cyclic AMP 1 (EPAC1) agonist, I942, regulates inflammatory gene expression in human umbilical vascular endothelial cells (HUVECs)

Wiejak

Basten

Luchowska-Stańska

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Exchange protein activated by cyclic AMP (EPAC1) suppresses multiple inflammatory actions in vascular endothelial cells (VECs), partly due to its ability to induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene, the protein product of which inhibits interleukin 6 (IL6) signalling through the JAK/STAT3 pathway. Here, for the first time, we use the non-cyclic nucleotide EPAC1 agonist, I942, to determine its actions on cellular EPAC1 activity and cyclic AMP-regulated gene expression in VECs. We demonstrate that I942 promotes EPAC1 and Rap1 activation in HEK293T cells and induces SOCS3 expression and suppresses IL6-stimulated JAK/STAT3 signalling in HUVECs. SOCS3 induction by I942 in HUVECs was blocked by the EPAC1 antagonist, ESI-09, and EPAC1 siRNA, but not by the broad-spectrum protein kinase A (PKA) inhibitor, H89, indicating that I942 regulates SOCS3 gene expression through EPAC1. RNA sequencing was carried out to further identify I942-regulated genes in HUVECs. This identified 425 I942-regulated genes that were also regulated by the EPAC1-selective cyclic AMP analogue, 007, and the cyclic AMP-elevating agents, forskolin and rolipram (F/R). The majority of genes identified were suppressed by I942, 007 and F/R treatment and many were involved in the control of key vascular functions, including the gene for the cell adhesion molecule, VCAM1. I942 and 007 also inhibited IL6-induced expression of VCAM1 at the protein level and blocked VCAM1-dependent monocyte adhesion to HUVECs. Overall, I942 represents the first non-cyclic nucleotide EPAC1 agonist in cells with the ability to suppress IL6 signalling and inflammatory gene expression in VECs.

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“…Besides, it has been reported that activation of Epac1 induces SOCS3 gene expression in various types of cells, i.e. cardiocyte (27), vascular endothelial cell (28) and retinal ganglion cell (29). In this study, we observed that Epac activation significantly up-regulated the expression of SOCS3 while inhibited the expression of p-STAT3 and MCP-1 in kidney tissues (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the manipulation of SOCS3 expression would be imperative and is a therapeutic target for DN. Additionally, it has been reported that Epac1 induces SOCS3 gene expression in various types of cells, including cardiocyte (27), vascular endothelial cells (28) and retinal ganglion cells (29). Based on these perspectives, we hypothesized that activation of Epac may protect against the inflammation injury by targeting SOCS3 gene expression in the context of hyperglycemia.…”

Section: Introductionmentioning

confidence: 99%

Epac ameliorates tubulointerstitial inflammation in diabetic nephropathy via C/EBPβ/SOCS3/STAT3 pathway

Yang

Zhang

Wang

et al. 2020

Preprint

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Background: Tubulointerstitial inflammation plays a pivotal role in the progression of diabetic nephrology (DN), and tubular cells act as the driving force in the inflammation cascade. The aim of the study is to investigate whether activation of Epac alleviates tubulointerstitial inflammation through SOCS3/JAK/STAT3 pathway under DN. Methods: The kidney morphological changes and the level of oxidative stress were observed in db/db mice treated with Epac agonist (8-pCPT-2’-O-Me-cAMP). The expression of inflammatory cytokines, fibrosis markers, C/EBPβ, SOCS3 and p-STAT3 in renal tissues were assessed. In in vitro study, the changes of above genes and proteins were also detected in human proximal tubular cell line (HK-2) incubated with high glucose (HG) with and without Epac agonist. Overexpression of SOCS3 plasmid, SOCS3 siRNA and C/EBP-β siRNA were employed and the translocation of C/EBP-β and p-STAT3 were observed by immunofluorescence. Macrophage migration assay were detected in Transwell system. Results: In db/db mice, we observed that the expression of MCP-1 was up-regulated in renal tubular cells, which concurrent with increased influx of macrophages, cytokines production (MCP-1, TNF-α, and IL-6), and tubulointerstitial fibrosis. Moreover, we also found that these changes were accompanied by reduced C/EBP-β expression and increased SOCS3 and phosphorylated STAT3 (p-STAT3) expression. However, after treated db/db mice with 8-O-cAMP, an Epac activator, the expression of SOCS3 further up-regulated while other protein expression profile was partially reversed. In vitro , high glucose (30mM, HG) treatment down-regulated C/EBP-β expression while increased SOCS3, p-STAT3 and MCP-1 expression in HK-2 cells; Activation of Epac by 8-O-cAMP further increased the gene and protein expression of SOCS3 while reversed the changes of the other proteins. Mechanistically, under HG ambience, knockdown of C/EBP-β or SOCS3 in HK-2 cells partially blocked the inhibitory effect of Epac activation on MCP-1 expression. Furthermore, 8-O-cAMP treatment enhanced the nuclear-translocation of C/EBP-β and further increased the transcription of SOCS3 gene, which decreased MCP-1 expression through inhibiting the phosphorylation of STAT3 in HK-2 cells. Conclusions: These data indicate that Epac ameliorates tubulointerstitial inflammation in DN at least partially through C/EBPβ/SOCS3/STAT3 pathway. Therefore, Activation of Epac by 8-O-cAMP may be a novel therapeutic strategy for DN.

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Epac activation inhibits IL-6-induced cardiac myocyte dysfunction

Cited by 17 publications

References 43 publications

Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice

Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice

The novel exchange protein activated by cyclic AMP 1 (EPAC1) agonist, I942, regulates inflammatory gene expression in human umbilical vascular endothelial cells (HUVECs)

Epac ameliorates tubulointerstitial inflammation in diabetic nephropathy via C/EBPβ/SOCS3/STAT3 pathway

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