Targeting the elabela/apelin-apelin receptor axis as a novel therapeutic approach for hypertension

Abstract

Hypertension is the leading risk factor for global mortality and morbidity and those with hypertension are more likely to develop severe symptoms in cardiovascular and cerebrovascular system, which is closely related to abnormal renin-angiotensin system and elabela/apelin-apelin receptor (APJ) axis. The elabela/apelin-APJ axis exerts essential roles in regulating blood pressure levels, vascular tone, and cardiovascular dysfunction in hypertension by counterbalancing the action of the angiotensin II/angiotensin II type 1 receptor axis and enhancing the endothelial nitric oxide (NO) synthase/NO signaling. Furthermore, the elabela/apelin-APJ axis demonstrates beneficial effects in cardiovascular physiology and pathophysiology, including angiogenesis, cellular proliferation, fibrosis, apoptosis, oxidative stress, and cardiovascular remodeling and dysfunction during hypertension. More importantly, effects of the elabela/apelin-APJ axis on vascular tone may depend upon blood vessel type or various pathological conditions. Intriguingly, the broad distribution of elabela/apelin and alternative isoforms implicates its distinct functions in diverse cardiac and vascular cells and tissue types. Finally, both loss-of-function and gain-of-function approaches have defined critical roles of the elabela/apelin-APJ axis in reducing the development and severity of hypertensive diseases. Thus, targeting the elabela/ apelin-APJ axis has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of hypertension, and an increased understanding of cardiovascular actions of the elabela/apelin-APJ axis will help to develop effective interventions for hypertension. In this review, we focus on the physiology and biochemistry, diverse actions, and underlying mechanisms of the elabela/apelin-APJ axis, highlighting its role in hypertension and hypertensive cardiovascular injury and dysfunction, with a view to provide a prospective strategy for hypertensive disease therapy.

MicroRNA-122-5p Aggravates Angiotensin II-Mediated Myocardial Fibrosis and Dysfunction in Hypertensive Rats by Regulating the Elabela/Apelin-APJ and ACE2-GDF15-Porimin Signaling

“…Its agonists are being considered therapeutic agents to modulate cardiovascular homeostasis in adults. The new endogenous peptide ligand for APJ, ELA, has been expected to become a biomarker and drug of cardiovascular diseases [13]. Circulating ELA and apelin levels were decreased in patients with essential hypertension and general hypertension [13].…”

“…The new endogenous peptide ligand for APJ, ELA, has been expected to become a biomarker and drug of cardiovascular diseases [13]. Circulating ELA and apelin levels were decreased in patients with essential hypertension and general hypertension [13]. The ELA/ apelin-APJ axis is widely expressed in cardiovascular system, and exerts a variety of important functions, including vascular tone regulation, angiogenesis, and heart morphogenesis [13], suggesting that determination and modulation of the activity of ELA/apelin-APJ axis have predictive and therapeutic value.…”

“…Circulating ELA and apelin levels were decreased in patients with essential hypertension and general hypertension [13]. The ELA/ apelin-APJ axis is widely expressed in cardiovascular system, and exerts a variety of important functions, including vascular tone regulation, angiogenesis, and heart morphogenesis [13], suggesting that determination and modulation of the activity of ELA/apelin-APJ axis have predictive and therapeutic value. In the current study, rAAV-miR-122-5p treatment further led to downregulation of ELA in hearts of hypertensive rats.…”

“…Previously, apelin was thought to be the only ligand for apelin receptor (APJ), while elabela (ELA) was identified as a second endogenous ligand for the APJ. The ELA/apelin-APJ axis exerts essential roles in regulating blood pressure levels and cardiovascular dysfunction during hypertension by counterbalancing the action of RAS [13] implying an interaction between miR-122-5p and the ELA/apelin-APJ axis However, the exact mechanisms and underlying pathways of miR-122-5p in hypertensive cardiac injury remain to be identified. In the present study, we discovered a previously unrecognized role of miR-122-5p in the development of cardiac fibrosis and dysfunction in the context of hypertension, highlighting a novel molecular mechanism of miR-122-5p during hypertension with potential therapeutic relevance.…”

The Role of Apelin–APJ System in Diabetes and Obesity

“…Evidences revealed the role of Elabela in homeostasis, cell signaling, energy metabolism, and cell aging. Serum Elabela is associated with several diseases, such as diabetes ( 29 ), myocardial infarction ( 30 ), hypertension ( 31 ), and kidney disease ( 32 ). Notably, Elabela level is also related to the prognosis of these diseases.…”