MicroRNAs involve in bicuspid aortic aneurysm: pathogenesis and biomarkers

(2021) 16:230 Jia et al. J Cardiothorac Surg https://doi.org/10.1186/s13019-021-01613-9 Open Access REVIEW MicroRNAs involve in bicuspid aortic aneurysm: pathogenesis and biomarkers Hao Jia1†, Le Kang1†, Zhen Ma2†, Shuyang Lu1, Ben Huang1, Chunsheng Wang1*, Yunzeng Zou2* and Yongxin Sun1* Abstract The incidence of bicuspid aortic valves (BAV) is high in the whole population, BAV-related thoracic aortic aneurysm (TAA) is accompanied by many adverse vascular events. So far, there are two key points in dealing with BAV-related TAA. First is fully understanding on its pathogenesis. Second is optimizing surgical intervention time. This review aims to illustrate the potential role of miRNAs in both aspects, that is, how miRNAs are involved in the occurrence and progression of BAV-related TAA, and the feasibilities of miRNAs as biomarkers. Keywords: miRNA, Aneurysm, Bicuspid aortic valve, Mechanism, Biomarker Highlights 1. MiRNA involved in highly heterogeneous etiology of BAV-related TAA. 2. In BAV-related TAA, miRNA mainly targets ECM, VSMC and ECs. 3. MiRNA can be used as a biomarker to guide the timing of TAA surgery. Introduction Bicuspid aortic valve (BAV) is one of the most prevalent congenital heart malformation with overall incidence of 1% to 2% [1]. This malformation is closely associated with a high risk of aortic valve dysfunction and thoracic aortic complications. In patients with BAV, the progressive dilation of thoracic aorta will be a critical focus complication. *Correspondence: ; ; † Hao Jia, Le Kang and Zhen Ma have contributed equally to the research 1 Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, 1069 Xietu Road, 200032 Shanghai, People’s Republic of China 2 Central Laboratory of Cardiovascular Institute, Zhongshan Hospital, Fudan University, 1069 Xietu Road, 200032 Shanghai, People’s Republic of China Without effective surgical intervention, progressive aortic dilation can result in aortic dissection (mortality of which averages 25% in its acute Stanford A-type) [2] and aortic rupture (mortality of which averages 57% in emergency operations) [3]. To avoid such catastrophic vascular events, essential treatments to progressive aortic dilation is aorta and/or aortic valves replacement. Although surgical method improved greatly the prognosis of thoracic aortic aneurysm (TAA), uncertainties still remained in decision of time to start surgical intervention, partly because the imaging diagnosis and morphological presentation of TAA are not sufficient to give strong evidences for the timing of surgeries. According to a large clinical study in 2007, 59% of Type A aortic dissections occurred in patients with an aortic diameter of less than 5.5 cm, and 40% occurred in patients with an aortic diameter of less than 5.0 cm [4]. Furthermore, the adjacent distal aorta still has a potential risk of dilation after a successful aortic replacement surgery [5], resulting in reoperations that poses extra risk on the patients. Recent studies reveal complexing and unique pathogenesis about BAV-related TAA including gene mutations [6], hemodynamics, mechanical stress [7], oxidation and inflammation, and their interactions. As a research hotspot up-to-date, miRNA has attracted much attention © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jia et al. J Cardiothorac Surg (2021) 16:230 in regulating gene expression through translation repression and messenger RNA (mRNA) decay, which enables the abnormal expression of miRNA to participate in the occurrence and progression of various human diseases [8]. Especially, miRNA can be an important regulatory molecule in the studies of some diseases with high heterogeneity and unclear pathogenesis. In this review, we try to summarize functions of miRNA and relationships between miRNA and BAVrelated TAA; and to discuss potential applications of miRNA in diagnosis and treatment for BAV-related TAA. Biological function of miRNA miRNAs are a series of endogenous expression non-coding RNAs (ncRNA) that have a sequence-specific model guiding to the targets. They are classified into different families according to their seed sequences which are the main fragments binding to target genes [9]. Pre-miRNA is a semi-mature molecule with double strands to be separated. One strand is degraded to maintain the homeostasis of functional miRNA, the other strand functions actively to bind to specific regulating targets, including protein-coding mRNA and ncRNA [10]. miRNA cooperates with Argonaute (AGO) proteins to work as a functional complex [11]. AGO2 is ubiquitously intracellular expressed and participate in various of functions [12]. Domains in AGO are involved in the process of miRNA seed sequences recognizing target sites, and this process of recognition and binding is not highly conserved. In addition to strongest complementarity, there are other complementary ways with weak seed-match degrees [8]. The binding targets locate mainly within the 3’ untranslated regions (UTR) of mRNA, inducing translation inhibition and promotion of mRNA decay as main effects. Translation inhibition is achieved by assembling initiation factors and mRNA [13], and mRNA decay (major effects of miRNA) is conducted by enzymatic degradation followed by deadenylation of mRNA [14]. As a member of RNA, miRNA can be regulated by transcriptional promoting or inhibiting. What’ more, degradation rates and epigenetic repression can also influence miRNAs’ content. Post-transcriptional modifications of miRNA, such as uridylation, adenylated and oxidation [15–17], can change the stability and functions of miRNA. The functions and characteristics of miRNA described above support the involvement of miRNA in the highly heterogeneous pathogenesis of BAV-related TAA. In addition, most miRNAs have an average half-life of 119 h or slightly longer, but some also have a rapid change in their content [18]; moreover, miRNA remains highly stable in f (...truncated)