miR-564: A potential regulator of vascular smooth muscle cells and therapeutic target for aortic dissection
Graphical abstract
MiR-564 regulates the biological function of VSMC via targeting SKI and NRGN leading to mediating the onset and progression of aortic dissection.
Introduction
Cardiovascular diseases (CVDs) have high mortality and morbidity and are among the main threats to human health and life worldwide. Aortic dissection (AD), caused by rupture of the lining of the aorta and blood entry into the media membrane, is one of the most complex CVD [[1], [2], [3], [4], [5], [6], [7]]. AD has a high fatality rate, with an estimated annual incidence of 0.02%–0.05% [[8], [9], [10]]. In AD development, the most worrying consequence is rapid death caused by a complete rupture of the aorta, which reduces the blood supply to other organs, including the heart. In the clinic, the treatment of AD patients mainly comprises surgical operation, aiming to close the intimal tear and reconstruct the blood flow in the vascular occlusion area caused by the false lumen. However, the surgical treatment of trauma and its complications, not only can lead to secondary injury, but also cannot reverse the occurrence and development of AD. Therefore, early detection and intervention in the early stage of AD and prevention of recurrence after operation are of great significance for reducing mortality. However, important molecular targets which can be applied to the rapid diagnosis and treatment of AD have not been yet identified. Thus, there is an urgent need to identify novel targets for AD prevention and treatment. Human aortic vascular smooth muscle cells (VSMCs) are one of the main components of the vascular wall and play a crucial role in the pathogenesis of a variety of CVDs. Remodeling of VSMCs is earlier process associated with dilatation of the aorta. Furthermore, VSMCs dysfunction is considered one of the most significant factors leading to medial degeneration of vascular remodeling in AD [[11], [12], [13], [14], [15], [16], [17]]. Particularly, in AD progression, VSMCs undergo a phenotype switch from the contractile (differentiated) to the synthetic (dedifferentiated) phenotype, which presents enhanced proliferation and migration abilities, and reduced expression of differentiation markers [18]. Besides, another typical sign of the progression of AD is the occurrence and development of inflammation, such as the infiltration of macrophages and monocytes, or increased expression levels of inflammatory factors. Thereby, it has also been reported that inflammation, including inflammatory and endothelial cells localized within the walls of the aorta, plays an important role in AD [19]. Herein, we aimed to understand the mechanism of vascular remodeling to identify novel AD targets.
Noncoding (nc RNAs) plays an important role in the development of CVDs [20,21]. MicroRNAs (miRNAs) are a class of small non-coding RNAs that bind to the 3′ untranslated region (3’UTR) of downstream mRNAs and lead to their degradation. Emerging evidence demonstrated that miRNAs, which are abundant in vascular tissues, play a vital regulatory role in the occurrence and development of CVDs [[22], [23], [24]], including AD. Abnormal miRNA expression in AD has been shown in many studies. Wang et al. found that the expression of miR-107-5p is maintained at a high level in acute AD tissues. Further experiments proved that miR-107-5p was associated with proliferation and apoptosis in rat aortic smooth muscle cells (RASMCs) [25]. Duan et al. reported that the upregulation of miR-133a could potentially rescue acute aortic dissection (AAD) [26]. Wang et al. demonstrated that miR-134-5p can recruit STAT5B/ITGB1 to regulate AD [27]. In addition, miRNA also seems to regulate trigger and progression of AD by regulating the development of inflammation. Wang et al. proved that plenty of miRNA were differentially expressed in healthy and AD patients, and some of them are associated with inflammation via microarray analysis and bioinformatics [28]. Collectively, miRNAs possess the qualities to be promising targets in AD diagnosis and treatment.
Several studies have proved that miR-564 plays an important role in various cancer types via mediating cancer cell proliferation, invasion and death [[29], [30], [31], [32], [33]]. Meanwhile, it has been shown that miR-564 was down-regulated in TNFα-treated HUVECs [34]. However, the regulatory effect of miR-564 on VSMCs remains unknown, which prompted us to further study whether miR-564 could regulate the development of CVDs, such as AD. The aim of this study was to investigate the expression and distribution of miR-564 in AD tissues as well as its close relationship with AD. Furthermore, we aimed to explore its regulatory role in vascular remodeling in vivo by establishing a mouse model of AD. The regulatory role of miR-564 in the function of VSMCs and the underlying mechanism were studied in vitro. Our findings may provide a new regulatory strategy for AD and a potential therapeutic target for AD prevention.
Section snippets
Cell culture, treatment and transfection
The cells used throughout this study were examined for mycoplasma contamination. VSMCs (Human aortic vascular smooth muscle cells) (ATCC, Manassas, VA, USA) were authenticated using Short Tandem Repeat (STR) sequencing and grown in Dulbecco's modified Eagle's medium (DMEM) (SparkJade, Qingdao, China) supplemented with fetal bovine serum (FBS)(10%) (ExCell Bio, Shanghai, China), and 1% penicillin-streptomycin liquid (Millipore, Massachusetts, USA). VSMCs were cultured in humidified incubators at
Identification and characterization of miR-564
We detected the expression levels of miR-564 under clinical evaluation using qRT-PCR. In line with previous reports, we observed that the levels of miR-564 were approximately 11-fold downregulated in AD patients compared with those in healthy individuals (p = 0.0249) (Fig. 1A). Likewise, the FISH results verified that miR-564 was abundantly and differentially expressed in AD (Fig. 1B and C), in which α-SMA served as a marker of the tunica media. Next, we investigated miR-564 expression in the
Discussion
In recent years, great progress has been made in identifying the pathogenesis of chronic cardiovascular diseases. However, the regulatory mechanism of AD is still largely unknown, and there is a lack of reliable therapeutic targets for the treatment of AD. With the in-depth study of non-coding RNA, it has been demonstrated that ncRNAs are critically involved in the regulation of VSMCs and the development of AD. In this study, we identified miR-564 as a new mediator regulating the phenotypic
Funding
This work was supported by National Natural Science Foundation of China (No. 81870331) and The People's Livelihood Science and Technology Project of Qingdao (No. 21-1-4-rkjk-12-nsh).
Author contributions
Min Li: Investigation, Methodology, Software, Writing-Original draft preparation. Yanyan Yang: Investigation, Software. Jinbao Zong: Resources. Zhibin Wang: Resources. Shaoyan Jiang: Resources. Xiuxiu Fu: Resources. Xiangqin He: Resources. Xiaoxin Li: Investigation, Data curation. Qianqian Xue: Investigation, Resources. Jian-Xun Wang: Writing-Reviewing and Editing. Tao Yu: Conceptualization, Visualization, Supervision, Writing-Reviewing and Editing, Funding acquisition.
Declaration of Competing Interest
The authors have declared that no competing interest exists.
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These authors contributed equally to this paper.