Downregulation of miR-128 Ameliorates Ang II-Induced Cardiac Remodeling via SIRT1/PIK3R1 Multiple Targets.

Heqin Zhan,Wenzhuo Ma,Kaina Zhang,Shiyu Guo,Feng Huang,Qian Niu,Shan Mi,Zhenghang Zhao,Xumeng Han,Mingli Jiao

doi:10.1155/2021/8889195

Abstract

Recent studies reported that miR-128 was differentially expressed in cardiomyocytes in response to pathologic stress. However, its function and mechanism remain to be fully elucidated. The aim of the present study was to investigate the role of miR-128 in chronic angiotensin II (Ang II) infusion-induced cardiac remodeling and its underlying mechanism. The cardiac remodeling and heart failure in vivo were established in C57BL/6 mice by chronic subcutaneous Ang II delivery. Knocking down miR-128 was conducted in the hearts of the mice by intravenous injection of HBAAV2/9-miR-128-GFP sponge (miR-128 inhibitor). In vitro experiments of cardiac hypertrophy, apoptosis, and aberrant autophagy were performed in cultured cells after Ang II treatment or transfection of miR-128 antagomir. Our results showed that chronic Ang II delivery for 28 days induced cardiac dysfunction, hypertrophy, fibrosis, apoptosis, and oxidative stress in the mice, while the miR-128 expression was notably enhanced in the left ventricle. Silencing miR-128 in the hearts of mice ameliorated Ang II-induced cardiac dysfunction, hypertrophy, fibrosis apoptosis, and oxidative stress injury. Moreover, Ang II induced excessive autophagy in the mouse hearts, which was suppressed by miR-128 knockdown. In cultured cells, Ang II treatment induced a marked elevation in the miR-128 expression. Downregulation of miR-128 in the cells by transfection with miR-128 antagomir attenuated Ang II-induced apoptosis and oxidative injury probably via directly targeting on the SIRT1/p53 pathway. Intriguingly, we found that miR-128 inhibition activated PIK3R1/Akt/mTOR pathway and thereby significantly damped Ang II-stimulated pathological autophagy in cardiomyocytes, which consequently mitigated cell oxidative stress and apoptosis. In conclusion, downregulation of miR-128 ameliorates Ang II-provoked cardiac oxidative stress, hypertrophy, fibrosis, apoptosis, and dysfunction in mice, likely through targeting on PIK3R1/Akt/mTORC1 and/or SIRT1/p53 pathways. These results indicate that miR-128 inhibition might be a potent therapeutic strategy for maladaptive cardiac remodeling and heart failure.

Highlights

Pathological cardiac remodeling is characterized by the gene phenotype changes of cardiomyocytes as well as abnormal cardiac morphology and functions
Our preliminary experiments showed that the miR-128 expression was dramatically enhanced in Ang IIstimulated H9c2 cells or mouse left ventricle, and we proposed that the downregulation of miR-128 might play a beneficial role in angiotensin II (Ang II)-induced cardiac remodeling
On the contrary, silencing miR-128 with miR-128 sponge significantly reversed Ang II-induced increases in Left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal dimension systole (LVIDs), left ventricular volume during diastolic (LVVOLd), and left ventricular volume during systole (LVVOLs) as well as decreases in left ventricular posterior wall diastolic thickness (LVPWd), LVPWs, interventricular septum end-diastolic thickness (IVSd), interventricular septal end-systolic thickness (IVSs), left ventricular ejection fraction (LVEF), and LVFS (Table 2) and attenuated the increases in the cardiac mass index, the cross-sectional area, and CVF values induced by Ang II, suggesting that miR-128 knockdown in heart plays a beneficial role in Ang II-induced cardiac remodeling

Summary

Introduction

Pathological cardiac remodeling is characterized by the gene phenotype changes of cardiomyocytes as well as abnormal cardiac morphology and functions. This process involves progressive cardiomyocyte hypertrophy, accompanying enhanced apoptosis, fibrosis, and oxidative stress [1, 2]. Deficiency of efficient interventions restricts the treatment of HF since numerous alterations in molecules and genes related to cardiac remodeling [4], especially the molecular interactions in the gene transcriptome and posttranscriptional modification, have not been elaborated [5]. MicroRNAs (miRs) are noncoding single-stranded RNAs that are highly conserved in eukaryotes. They are able to recognize and complementarily bind to target mRNAs, causing posttranscriptional degradation of the target genes [6].

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