ELA

, also known as apela, is a newly identified signaling molecule that acts as a novel endogenous ligand for the apelin receptor (APJ) PMID 40588098PMID 40210118.

• Receptor Interaction: ELA binds to the APJ receptor, a G-protein-coupled receptor, to selectively phosphorylate specific serine residues at its C-terminus (e.g., Elabela-32 activates Ser335), resulting in distinct signaling profiles PMID 40588098.
• Physiological Homeostasis: ELA is involved in the regulation of vascular tone, fluid balance, and cardiac contractility PMID 40210118PMID 40588098.
• Disease Prevention: Deficiency of ELA has been shown to promote preeclampsia and cardiovascular malformations in preclinical models PMID 40588098.

• Exercise-Induced Secretion: ELA is considered an exerkine because physical activity, specifically aerobic exercise, stimulates its expression and secretion into the bloodstream PMID 40210118.
• Organ-to-Organ Crosstalk: While primarily secreted by the kidney, exercise-stimulated ELA enters the systemic circulation to regulate the function of the cardiovascular system via humoral mechanisms PMID 40210118.

• Cardiovascular Repair: ELA has demonstrated the potential to ameliorate myocardial injury, promote angiogenesis, and reduce cardiac fibrosis following myocardial infarction and ischemia/reperfusion injury PMID 40210118.
• Hypertension Management: Treatment with ELA significantly decreases diastolic blood pressure and reduces vascular inflammation and oxidative stress in hypertensive models PMID 40210118.
• Diabetic Cardiomyopathy (DCM): In diabetic models, ELA upregulates SIRT3 and its downstream antioxidant proteins, which reduces cardiomyocyte apoptosis and improves overall cardiac function PMID 40210118.
• Anti-Ferroptotic Effects: ELA can protect against angiotensin II-induced ferroptosis in cardiac microvascular endothelial cells by modulating the IL-6/STAT3/GPX4 signaling pathway PMID 39988270.
• Heart Failure: It has been shown to inhibit pressure overload-induced heart failure and mitigate cardiotoxicity induced by chemotherapy drugs like doxorubicin PMID 40210118.

Note: text from PMID 40210118 about ELA: Exercise has been demonstrated to promote the secretion of exerkines by the kidney. These exerkines regulate the function of the cardiovascular system through blood circulation. A new study found that ELABELA (ELA), a novel endogenous ligand for the apelin receptor (APJ), is mainly secreted by the kidney in mice. Exercise-stimulated increase in kidney secretion of ELA ameliorates myocardial injury . In myocardial infarction and cardiac I/R injury, tail vein injections of ELA in mice promoted angiogenesis, reduced cardiac fibrosis, and improved cardiac function [37]. ELA treatment significantly decreases diastolic blood pressure, reduces vascular inflammation and oxidative stress in hypertensive rats [38], and inhibits pressure overload-induced HF [39]. The interaction between the heart and kidney is mediated by exerkine endocytosis. As an exerkine derived from the kidney, ELA plays a role in regulating the kidney and cardiovascular systems through humoral mechanisms. This may represent a novel target for the treatment of cardiovascular diseases.

ELABELA (ELA) demonstrates therapeutic potential across multiple cardiovascular, renal, and neurological conditions, with evidence supporting its use in hypertension, heart failure, acute kidney injury, ischemic stroke, and pulmonary arterial hypertension. PMID 32740407PMID 36029072PMID 28137936PMID 33290073PMID 37433415

ELA functions as an endogenous ligand for the APJ receptor and exhibits vasodilatory, cardioprotective, and renoprotective effects when administered peripherally. PMID 32740407PMID 29350399 In pulmonary arterial hypertension, exogenous ELA administration significantly attenuated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in rat models. PMID 28137936 For acute kidney injury, modified ELA analogues (PEGylated and acylated forms) showed enhanced receptor binding, prolonged stability, and protective effects against ischemia-reperfusion injury and cisplatin-induced nephrotoxicity. PMID 33290073

ELA also demonstrates neuroprotective properties by inhibiting neuronal ferroptosis in cerebral ischemia/reperfusion injury, reducing brain infarction and improving neurobehavioral outcomes through activation of the NRF2/ARE antioxidative signaling pathway. PMID 36681202 In sepsis-induced myocardial dysfunction, the ELA-APJ axis reduced pyroptosis by promoting autophagy and decreasing oxidative stress. PMID 39241986

The primary limitation for clinical application is ELA's short half-life and requirement for parenteral administration. PMID 32740407 To address this, modified formulations including PEG-ELA-21, Fc-ELA-21, albumin-ELA-21, and acylated analogues have been developed with improved stability and efficacy. PMID 32740407PMID 33290073 These modifications enhance receptor binding capacity and plasma stability while maintaining therapeutic effects.

Circulating ELA levels may serve as a diagnostic biomarker for various cardiovascular diseases, as ELA expression is downregulated in conditions like pulmonary arterial hypertension, heart failure, and preeclampsia. PMID 37776977PMID 28137936PMID 37433415