The ACE2/Apelin Signaling, MicroRNAs, and Hypertension

Abstract

The renin-angiotensin aldosterone system (RAAS) plays a pivotal role in the development of hypertension. Angiotensin converting enzyme 2 (ACE2), which primarily metabolises angiotensin (Ang) II to generate the beneficial heptapeptide Ang-(1-7), serves as a negative regulator of the RAAS. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardiovascular protective peptide. The physiological effects of Apelin are exerted through binding to its receptor APJ, a seven-transmembrane G protein-coupled receptor that shares significant homology with the Ang II type 1 receptor (AT1R). The deregulation of microRNAs, a class of short and small noncoding RNAs, has been shown to involve cardiovascular remodeling and pathogenesis of hypertension via the activation of the Ang II/AT1R pathway. MicroRNAs are linked with modulation of the ACE2/Apelin signaling, which exhibits beneficial effects in the cardiovascular system and hypertension. The ACE2-coupled crosstalk among the RAAS, the Apelin system, and microRNAs provides an important mechanistic insight into hypertension. This paper focuses on what is known about the ACE2/Apelin signaling and its biological roles, paying particular attention to interactions and crosstalk among the ACE2/Apelin signaling, microRNAs, and hypertension, aiming to facilitate the exploitation of new therapeutic medicine to control hypertension.

Figure 1

The crosstalk between ACE2/Apelin signaling and miRNAs in hypertension. On one hand, the miR-145 and miR-27a/b suppress the action of ACE/Ang II/AT1R, whereas miR-143 and miR-421 serve as negative regulators of ACE2 to modulate the balance between Ang II degradation and Ang-(1-7) generation. Overexpression of miR-155 inhibits the effects mediated by Ang II/AT1R signaling while Ang II regulates miR-138 and miR-132/212 expression via its receptor AT1R, contributing to cardiovascular hypertrophy and remodeling and elevated blood pressure. In contrast, Ang-(1-7) promotes the level of miR-146a, which blocks inflammation and cardiovascular remodeling. On the other hand, the Apelin/APJ signaling regulates the expression of miR-133a, miR-208, and miR-1, functioning as negative regulators for cardiac hypertrophy and contractile function. Moreover, the Apelin/APJ ameliorates cardiovascular hypertrophy and remodeling by modulating miR-424/-503-FGF signaling. ACE: angiotensin converting enzyme; ACE2: angiotensin converting enzyme 2; Ang II: angiotensin; AT1R: angiotensin II type 1 receptor; miRNAs: microRNAs; FGF2: fibroblast growth factor 2; FGFR1: fibroblast growth factor receptor 1.