The Elabela-APJ axis: a promising therapeutic target for heart failure

Abstract

Heart failure (HF) is a growing epidemic with high morbidity and mortality at an international scale. The apelin-APJ receptor pathway has been implicated in HF, making it a promising therapeutic target. APJ has been shown to be activated by a novel endogenous peptide ligand known as Elabela (ELA, also called Toddler or Apela), with a critical role in cardiac development and function. Activation of the ELA-APJ receptor axis exerts a wide range of physiological effects, including depressor response, positive inotropic action, diuresis, anti-inflammatory, anti-fibrotic, and anti-remodeling, leading to its cardiovascular protection. The ELA-APJ axis is essential for diverse biological processes and has been shown to regulate fluid homeostasis, myocardial contractility, vasodilation, angiogenesis, cellular differentiation, apoptosis, oxidative stress, cardiorenal fibrosis, and dysfunction. The beneficial effects of the ELA-APJ receptor system are well-established by treating hypertension, myocardial infarction, and HF. Additionally, administration of ELA protects human embryonic stem cells against apoptosis and stress-induced cell death and promotes survival and self-renewal in an APJ-independent manner (X receptor) via the phosphatidylinositol 3-kinase/Akt pathway, which may provide a new therapeutic approach for HF. Thus, targeting the ELA-APJ axis has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of HF. An increased understanding of cardiovascular actions of ELA will help to develop effective interventions. This article gives an overview of the characteristics of the ELA-apelin-APJ axis and summarizes the current knowledge on its cardioprotective roles, potential mechanisms, and prospective application for acute and chronic HF.

Roles of MicroRNA-122 in Cardiovascular Fibrosis and Related Diseases

“…3) [1,6,9,10]. Recently, administration of a miR-122 inhibitor was shown to reduce the key transforming growth factor-β (TGF-β)-induced fibrotic signaling pathway, promotes collagen synthesis and stimulates fibrinogenesis, consequently resulting in the accumulation of fibroblasts and extracellular matrix (ECM), in hypertension and cardiovascular diseases [2,3,9,11]. In our previous study, we observed cardiovascular fibrosis, systolic dysfunction, cardiovascular remodeling and dysfunction in rats after transverse aortic constriction (TAC) or angiotensin II (Ang II) stimulation, and these Central roles of miR-122 in HF, hypertension, MI, atherosclerosis and atrial fibrillation.…”

“…There-fore, miR-122 can cause cardiovascular fibrosis and heart dysfunction, ultimately resulting in hypertension, atherosclerosis, MI and HF. MI myocardial infarction, HF heart failure, ROS reactive oxygen species, LVFS left ventricular fractional shortening, LVEF left ventricular ejection fraction effects were associated with increased levels of miR-122-5p, and reduced levels of SIRT6, elabela (ELA), angiotensin-converting enzyme 2 (ACE2) and phosphorylated adenosine 5 '-monophosphate-activated protein kinase (AMPK) ( Table 1) [1,2,6]. In uric acid-treated HK-2 tubular epithelial cells, treatment with miR-122 mimics markedly increased NLRP3 inflammasome activation by increasing the levels of BRCA1/ BRCA2-containing complex 3 (Table 1) [12].…”

“…Cardiovascular fibrosis, a vital cause of heart failure (HF), refers to the development of scar tissue in the injured heart and blood vessels due to an aberrant wound-healing response to injury or insult, and arises from enhanced inflammatory processes, uncontrolled cell proliferation and excessive oxidative stress [1][2][3]. Established fibrosis is a hallmark of chronic disease progression and a key contributor to cardiovascular stiffness and injury of the heart and vessels, ultimately leading to HF and vascular dysfunction [1][2][3][4]. Since wound healing and fibrotic responses to myocardial and vascular injury are multifactorial processes, current therapies that specifically target factors that contribute to only cardiovascular disease pathogenesis offer limited overall anti-fibrotic efficacy [3].…”

“…Since wound healing and fibrotic responses to myocardial and vascular injury are multifactorial processes, current therapies that specifically target factors that contribute to only cardiovascular disease pathogenesis offer limited overall anti-fibrotic efficacy [3]. Fibrosis-induced cardiovascular remodeling and injury are growing problems for improving strategies to prevent the development of fibrosis and reduce the mortality of HF [1][2][3].…”

Expression characteristics and regulatory mechanism of Apela gene in liver of chicken (Gallus gallus)

“…Phylogenetic analysis revealed Apela possesses a pair of conserved cysteines, and the last 13 residues are nearly invariant in all vertebrate species [8], which suggests a functional conservation of Apela-APJ pathway. When it comes to functionality, although Apela mRNA is expressed in human stem cells, prostate, and kidney [8,17], and Apela can promote angiogenesis and induce vasodilatation in mouse aorta through activating signal transduction pathways [17], and use as a pre-warning biomarker and a novel therapeutic target against progression of heart failure [18]. In addition, Apela can function as a regulatory RNA to regulate p53-mediated DNA damage-induced apoptosis (DIA) of mouse embryonic stem cells (mESCs) [19].…”