MiR-133b-3p attenuates angiotensin II-induced cardiac hypertrophy through the inhibition of apoptosis by targeting CDIP1

Abstract

MicroRNAs (miRNAs) have emerged as essential regulators that play important roles in the development of multiple systems. Recent studies have identified significant roles for miRNAs in the progression of cardiac hypertrophy. This study aims to investigate the effects of miR-133b-3p on angiotensin II (Ang II)-induced cardiac hypertrophy and apoptosis, as well as explore its underlying mechanisms. Our experimental results reveal that miR-133b-3p expression is significantly decreased in both animal and cell models of cardiac hypertrophy induced by Ang II. Overexpression of miR-133b-3p reverses the hypertrophic manifestations and apoptosis induced by Ang II. Through bioinformatics analysis and dual-luciferase reporter assays, CDIP1 (cell death inducing p53 target 1) is identified as a direct target of miR-133b-3p, and the overexpression of miR-133b-3p reduces CDIP1 expression. Additionally, CDIP1 silencing suppresses cardiomyocyte hypertrophy and apoptosis induced by Ang II. In summary, these results suggest that miR-133b-3p may serve as a potential diagnostic marker for cardiac hypertrophy and that the upregulation of miR-133b-3p inhibits cardiac hypertrophy by targeting CDIP1.

1. Introduction

Pathological cardiac hypertrophy is an adaptive response of the myocardium to pressure overload in the heart and is commonly observed in patients with hypertension, myocardial infarction, and valvular diseases [1,2]. Pathological cardiac hypertrophy often precedes overt heart failure and is an independent prognosticator of cardiovascular mortality [3]. The development of left ventricle hypertrophy is predominantly due to increased cardiomyocyte size. It is characterized by an overall increase in protein synthesis and fetal gene expression, including that of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) [4,5]. The renin-angiotensin system (RAS) is a key player in controlling homeostasis in the cardiovascular system, and angiotensin (Ang) II is the representative hormone in the RAS. As a vasopressor, Ang II contributes to pathological cardiac hypertrophy and the resulting heart failure indirectly via increased blood pressure and/or direct action on cardiomyocytes [6]. Recent reports have revealed that apoptosis is involved in regulating the progression of multiple cardiovascular diseases, including cardiac hypertrophy. However, the underlying mechanisms remain poorly understood [7].

MicroRNAs (miRNAs) are a group of endogenous noncoding single-stranded small-molecule RNAs comprising 21–23 nucleotides that play a master role in regulating gene expression [8]. Increasing evidence shows that miRNAs are involved in the posttranscriptional regulation of gene expression to maintain cardiac homeostasis [9]. Recent studies have indicated that changes in the expression levels of miRNAs may positively or negatively regulate cardiac hypertrophy and may be promising therapeutic targets for intervention. For example, miR-30d was decreased in both murine and neonatal rat cardiomyocyte models of hypertrophy, and overexpression of miR-30d ameliorated phenylephrine- and Ang II-induced cardiac hypertrophy [10]. Researchers have discovered that cholesterol-containing nanocarriers can efficiently deliver inhibitors of miR-182 into the heart to significantly suppress cardiac hypertrophy [11]. Additionally, systemic knockout of miR-27b attenuates Ang II-mediated pathological cardiac hypertrophy and myocardial fibrosis by targeting the FGF1 gene [12]. MiR-133b is frequently abnormally expressed in various kinds of human cancer, and its complex regulatory networks affect the tumorigenicity and development of malignant tumors [13–16]. Yu et al. [16] reported that the level of miR-133b-3p was significantly decreased during the postnatal heart growth period. In addition, it has also been reported that the overexpression of miR-133b-3p promoted the apoptosis of high glucose-treated mouse retinal microvascular endothelial cells [17]. However, whether miR-133b-3p could be a therapeutic target for pathological cardiac hypertrophy is undetermined.

Cell death-inducing p53 target 1 (CDIP1) is a protein that plays a role in apoptosis or programmed cell death, particularly in response to cellular stress and DNA damage [18]. CDIP1 induces apoptosis primarily through interactions with Bcl-2 family proteins, particularly proapoptotic proteins.