The network map of Elabela signaling pathway in physiological and pathological conditions

Dagamajalu, Shobha; Rex, Devasahayam Arokia Balaya; Suchitha, G P; Akhila, B.; Rainey, Jan K.; Prasad, T. S. Keshava

doi:10.1007/s12079-021-00640-4

Cited by 11 publications

(6 citation statements)

References 40 publications

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“…APJ has been reported as a predominant receptor of ELA and Apelin (6,34). One main downstream signaling pathway of APJ consists of Akt, mTOR, and P70S6K (35), which primarily regulate cell proliferation, apoptosis, and migration. As expected, compared with sham control, APJ expression was significantly increased in the MI group (2.56-fold), and it was more increased in the MIA group (P < 0.01, compared with the MI group) and further elevated in the MIAE group (P < 0.01, compared with the MIA group; Fig.…”

Section: Resultsmentioning

confidence: 99%

ELABELA-APJ-Akt/YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats

Yao

Ren

et al. 2023

Medicine &Amp; Science in Sports &Amp; Exercise

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PurposeThe aim of this study was to investigate the function and mechanisms of ELABELA (ELA) in the aerobic exercise-induced antiapoptosis and angiogenesis of ischemic heart.MethodsThe myocardial infarction (MI) model of Sprague–Dawley rat was established by the ligation of the left anterior descending coronary artery. MI rats underwent 5 wk of Fc-ELA-21 subcutaneous injection and aerobic exercise training using a motorized rodent treadmill. Heart function was evaluated by hemodynamic measures. Cardiac pathological remodeling was evaluated by Masson’s staining and the calculation of left ventricular weight index. Cell proliferation, angiogenesis, and Yes-associated protein (YAP) translocation were observed by immunofluorescence staining. Cell apoptosis was analyzed by TUNEL. Cell culture and treatment were used to elucidate the molecular mechanism of ELA. Protein expression was detected by Western blotting. Angiogenesis was observed by tubule formation test. One-way or two-way ANOVA and Student’s t-test were used for statistical analysis.ResultsAerobic exercise stimulated the endogenous ELA expression. Exercise and Fc-ELA-21 intervention significantly activated APJ-Akt-mTOR-P70S6K signaling pathway, kept more cardiomyocytes alive, and increased angiogenesis, so as to inhibit the cardiac pathological remodeling and improved the heart function of MI rats. Fc-ELA-32 also had the cellular and functional cardioprotective activities in vivo. In vitro, ELA-14 peptide regulated the phosphorylation and nucleoplasmic translocation of YAP and activated the APJ-Akt signaling pathway so as to increase the proliferation of H9C2 cells. Moreover, the antiapoptosis and the tubule formation of HUVECs were also enhanced by ELA-14, whereas the inhibition of Akt activity weakened such effects.ConclusionsELA is a potential therapeutic member that plays a key role through APJ-Akt/YAP signaling axis in aerobic exercise-induced cardioprotection of MI rats.

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Section: Resultsmentioning

confidence: 99%

ELABELA-APJ-Akt/YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats

Yao

Ren

et al. 2023

Medicine &Amp; Science in Sports &Amp; Exercise

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“…Our results found that ELA-32 could treat TGF-β1-induced EMT of HPMCs from the aspects of morphology and protein expression. The ELA-mediated activation of the PI3K/AKT pathway produces protective effects in kidney disease ( Dagamajalu et al, 2022 ). However, the activation of this pathway promotes the occurrence of PF in the peritoneal tissues of patients on PD.…”

Section: Discussionmentioning

confidence: 99%

Elabela Attenuates the TGF-β1-Induced Epithelial-Mesenchymal Transition of Peritoneal Mesothelial Cells in Patients Receiving Peritoneal Dialysis

Xie

et al. 2022

Front. Pharmacol.

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Peritoneal fibrosis (PF), a common complication in patients receiving peritoneal dialysis (PD), is primarily caused by the epithelial-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs). PF is the main reason for patients on PD to withdraw from PD. Effective treatment is unavailable for this complication at present. Elabela (ELA) is a polypeptide hormone secreted by the vascular endothelium and kidney. Peptide hormones ELA and apelin (APLN) have various protective effects on the cardiovascular and urinary systems and have potential therapeutic effects on organ fibrosis. ELA and APLN are less studied in PD population. Here, we aimed to investigate the clinical significance of ELA in patients on PD and to evaluate the therapeutic effect of ELA on EMT of HPMCs. Compared with those in patients with stage 5 chronic kidney disease who are not on dialysis, serum ELA levels in patients on PD increased with the improvement of residual renal function at PD duration <36 months and decreased to pre-dialysis levels at PD duration ≥36 months, suggesting that dialysis duration is the main risk factor affecting serum ELA levels in patients on PD. In addition, serum APLN levels decreased in the early stage of PD and recovered to the pre-dialysis level with the prolongation of dialysis time. Notably, serum APLN levels were positively correlated with dialysis duration in patients undergoing PD. To establish the EMT model, we stimulated HPMCs using transforming growth factor-beta 1 (TGF-β1) in cell experiments performed in vitro. ELA-32 treatment reversed the TGF-β1-induced reduction in the expression of the epithelial cell marker and suppressed the expression of mesenchymal cell markers by inhibiting the phosphorylation of SMAD2/3, ERK1/2, and AKT. Therefore, our findings imply that ELA-32 can interfere with the EMT of HPMCs by inhibiting the activation of the TGF-β/SMAD2/3, ERK1/2, and AKT pathways, providing novel insights on the potential therapeutic use of ELA for treating PD-related PF.

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“…More recently, a second endogenous ligand for APJ was discovered and named Toddler/ELABELA. Mature ELABELA is a 32 amino acid peptide found in the prostate, kidney, heart and blood vessels 8 . Apelin-13 and ELABELA-32 can be spontaneously modified by cyclization of the glutamine in N-terminus to produce pyroglutamylated apelin-13 (Pyr-apelin-13) or ELABELA-32 (Pyr-ELABELA-32), potentially increasing their plasma stability [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

“…Mature ELABELA is a 32 amino acid peptide found in the prostate, kidney, heart and blood vessels 8 . Apelin-13 and ELABELA-32 can be spontaneously modified by cyclization of the glutamine in N-terminus to produce pyroglutamylated apelin-13 (Pyr-apelin-13) or ELABELA-32 (Pyr-ELABELA-32), potentially increasing their plasma stability [8][9][10] . In recent years, the apelinergic system has emerged as a potential candidate for its beneficial role in angiogenesis, and on cardiovascular and metabolic functions.…”

Section: Introductionmentioning

confidence: 99%

The apelinergic system accelerates skin repair of full-thickness excisional wounds in a diabetic murine model

Geraldes,

Robillard,

Théroux

et al. 2024

Preprint

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Introduction: Chronic wounds are a serious complication of diabetes. Multiple components in the healing process are impaired by diabetes, creating hard-to-heal or non-healing wounds, increasing the risk of infection, enlargement and amputation. Altered angiogenesis is a major contributor of delayed healing process in diabetic wounds. The apenilergic system (APJ/Apelin/ELABELA) is an activator of the angiogenic response in endothelial cells, and apelin treatment has been shown to improve vascular density in animal models of ischemia. This study explored the impact of Pyr-apelin-13 and Pyr-ELABELA-32 on wound healing processes in diabetic mice and on fibroblast function. Methods: Two full-thickness excisional wounds were created on the mid-back of nondiabetic and diabetic mice. Diabetic mice received topical application of Pyr-apelin-13 or Pyr-ELABELA-32 daily for 14 days, and wounds were individually photographed to measure global wound closure and healing process. In vitro, fibroblasts were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Cell migration and proliferation assays were performed following either Pyr-apelin-13 or Pyr-ELABELA-32 stimulation. Results: Fourteen days post-injury, global wound closure was improved in diabetic mice receiving Pyr-apelin-13 or Pyr-ELABELA-32 compared to untreated diabetic mice. Wound treatment with Pyr-apelin-13 and Pyr-ELABELA-32 improved re-epithelialization and angiogenesis, reduced inflammation and promoted collagen synthesis in diabetic scar tissue. In cultured fibroblasts, Pyr-apelin-13 and Pyr-ELABELA-32 stimulation induced cell migration and proliferation through Akt and ERK signaling pathways under both NG or HG concentrations and hypoxia exposure. Conclusion: Our results demonstrated the therapeutic potential of the endogenous ligands of APJ, apelin and ELABELA, for the treatment of diabetic wounds.

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The network map of Elabela signaling pathway in physiological and pathological conditions

Cited by 11 publications

References 40 publications

ELABELA-APJ-Akt/YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats

ELABELA-APJ-Akt/YAP Signaling Axis: A Novel Mechanism of Aerobic Exercise in Cardioprotection of Myocardial Infarction Rats

Elabela Attenuates the TGF-β1-Induced Epithelial-Mesenchymal Transition of Peritoneal Mesothelial Cells in Patients Receiving Peritoneal Dialysis

The apelinergic system accelerates skin repair of full-thickness excisional wounds in a diabetic murine model

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