Lnc-C2orf63-4-1 Confers VSMC Homeostasis and Prevents Aortic Dissection Formation via STAT3 Interaction.

Song Zhang,Yunlong Gao,Yongtai Gong,Hui Yu,Yue Li,Sen Yan,Shiqi Zhao,Yingchun Luo,Yun Zhou,Xuexin Jin,Xinbo Zhao,Yun Zhang,Yue Yuan,Wei Xu,Danghui Sun,Xuejie Han

doi:10.3389/fcell.2021.792051

Abstract

Emerging evidence indicates that long non-coding RNAs (lncRNAs) serve as a critical molecular regulator in various cardiovascular diseases. Here, we aimed to identify and functionally characterize lncRNAs as potential mediators in the development of thoracic aortic dissection (TAD). We identified that a novel lncRNA, lnc-C2orf63-4-1, was lowly expressed in aortic samples of TAD patients and angiotensin II (Ang II)-challenged vascular smooth muscle cells (VSMCs), which was correlated with clinically aortic expansion. Besides, overexpression of lnc-C2orf63-4-1 significantly attenuated Ang II-induced apoptosis, phenotypic switching of VSMCs and degradation of extracellular matrix both in vitro and in vivo. A customized transcription factor array identified that signal transducer and activator of transcription 3 (STAT3) functioned as the main downstream effector. Mechanistically, dual-luciferase report analysis and RNA antisense purification (RAP) assay indicated that lnc-C2orf63-4-1 directly decreased the expression of STAT3, which was depend on the reduced stabilization of STAT3 mRNA. Importantly, up-regulation of STAT3 efficiently reversed the protective role of lnc-C2orf63-4-1 against Ang II-mediated vascular remodeling. Therefore, lnc-C2orf63-4-1 negatively regulated the expression of STAT3 and prevented the development of aortic dissection. Our study revealed that lnc-C2orf63-4-1 played a critical role in vascular homeostasis, and its dysfunction exacerbated Ang II-induced pathological vascular remodeling.

Highlights

Thoracic aortic dissection (TAD) is the most serious form of acute aortic syndrome with an incidence of about 15 cases per 100,000/year (Mussa et al, 2016)
To validate the gene expression profiles obtained via long non-coding RNAs (lncRNAs) highthroughput sequencing (HTS), we assessed and compared the expressions of seven target genes in aortic specimens obtained from the 24 thoracic aortic dissection (TAD) patients and 15 normal aortic individuals
We identified an uncharacterized lncRNA, lncC2orf63-4-1, which was down-regulated in the aorta of TAD patients and functionally required for the vascular remodeling

Summary

Introduction

Thoracic aortic dissection (TAD) is the most serious form of acute aortic syndrome with an incidence of about 15 cases per 100,000/year (Mussa et al, 2016). Under pathological stimulation, decreased levels of lnc-C2orf bind to the promoter region of STAT3 resulting in enhancement of STAT3 mRNA stabilization, which can activate downstream apoptosis signaling (indicated by elevated BAX and decreased BCL2 levels), matrix metalloproteinase family (indicated by elevated MMP-2 and MMP-9 levels) and interstitial fibrosis factors (indicated by elevated type I and type III collagen levels). Taken together, these events trigger smooth muscle cell apoptosis, degradation of ECM, and fibrosis, which induces vascular remodeling and aggravating AAD development. It is essential to obtain a better understanding of the cellular mechanisms and regulatory networks driving TAD development and progression to identify novel therapeutic targets

Objectives

Methods

Results

Conclusion