Potency of miR-144-3p in promoting abdominal aortic aneurysm progression in mice correlates with apoptosis of smooth muscle cells
Graphical abstract
Introduction
Abdominal aortic aneurysm (AAA) is a life-threatening disease that is most often diagnosed in individuals with certain risk factors, including increasing age, male gender, and smoking [1]. The high mortality from AAA in developed countries, and especially so in developing countries, places a great global burden of health care, which highlights the need for better diagnostic markers and interventions. Major histopathological characteristics of AAA consist of chronic inflammation featured with apoptosis of vascular smooth muscle cells (VSMCs) as well as dysfunction and loss of endothelial cells [[2], [3], [4]]. SMCs are the predominant cells in the media of the normal aortic wall, and are responsible for maintaining aortic structure and functions [5]. In AAA, there is decreased density of healthy SMCs, and elevated secretion of myosin-11, a specific protein maker of degeneration of SMCs in the aortic wall [6]. In general, the progressive loss of SMCs disrupts the vascular structural integrity, which mainly occurs via a process of SMC apoptosis [7]. This concept presents potential molecular targets for urgently needed new interventions against the cellular mechanisms driving AAA development.
Among the numerous noncoding microRNAs (miRNAs), the hairpin miR-144-3p is the most extensively studied, due to its involvement in diverse pathologies. One of its known functions of miR-144-3p is to can inhibit the protein translation and expression of tropoelastin (TE) expression by binding to the 3′-untranslated region (3′-UTR) of its messenger RNA (mRNA) in aortic smooth muscle cells (ASMCs) [8]. In the context of diabetic retinopathy, miR-144-3p has been demonstrated to inhibit proliferation of microvascular epithelial cells by downregulating fibroblast growth factor 6 [9]. Of note, the regulatory role of miR-144-3p in VSMCs has been deciphered by targeting forkhead box protein F1 [10]. Pilot research showed that miR-144-3p was significantly upregulated in peripheral blood mononuclear cells (PBMCs) and aneurysmal tissues of diabetic patients with AAA [11]. The current study hereby aimed to unravel the potential functional role of miR-144-3p in SMCs in the context of AAA. Historical literature reports showed that overexpression of enhancer of zeste homolog 2 (EZH2) facilitated proliferation, and migration, and decreased the apoptosis rate of human pulmonary arterial smooth muscle cells (PASMCs) [12], and that knockdown of EZH2 resulted in loss of vascular smooth muscle cells (VSMCs) [13]. Moreover, EZH2 has been proposed as a potential target in AAA treatment due to its downregulation in AAA tissue samples [14]. Interestingly, previous work has also shown that EZH2 could trigger reduced expression of p21 in gastric cancer cells to regulate the progression of gastric cancer [15]. p21 protein is a cyclin-dependent kinase-inhibitory protein that plays a key role in controlling cell cycle progression and proliferation [16]. Indeed, activation of the adenosine 5′-monophosphate-activated protein kinase-p53-p21 pathway plays an important role in inhibiting the proliferation of PAMSCs [17]. Notably, p21-mediated VSMC senescence facilitates the transcriptional activation of monocyte chemotactic protein-1/C-C motif chemokine 2 (MCP-1/CCL2), which may promote inflammatory cell recruitment and vascular inflammation in AAA [18]. Some target genes of miR-144-3p have already been confirmed, such as cyclin-dependent kinase inhibitor 2D [19] and adenosine triphosphate binding cassette transporter [20]. Nevertheless, it is not previously reported that EZH2 is a target gene for miR-144. Consideration of the above studies suggests a possibly causal interaction among miR-144-3p, EZH2 and p21 in the pathogenesis of AAA.
In this study, we investigated the association and function of miR-144-3p, EZH2 and p21 interactions in human ASMCs (HASMCs) and clinical AAA. We found that high expression of miR-144-3p and downregulated EZH2 expression in AAA tissues from patients and in a mouse model of AAA. We then confirmed that miR-144-3p could target and negatively regulate EZH2 expression by binding to the 3′-UTR of EZH2 mRNA, whereas overexpression of EZH2 and inhibition of p21 could reverse the effect of miR-144-3p on HASMC proliferation and apoptosis, thus presenting a novel pathway contributing to the occurrence of AAA.
Section snippets
MiR-144-3p was highly expressed in abdominal aortic tissues from patients with AAA and in vivo/in vitro AAA models
Nowadays, a growing body of research suggests that miR-144-3p plays an essential role in tumorigenesis [21,22], and previously, microarray data have shown that miR-144-3p was robustly overexpressed in aortic tissue specimens from patients with AAA [23]. To evaluate the clinical correlation between miR-144-3p expression level and AAA, we measured the expression of miR-144-3p in pathological abdominal aortic tissues and adjacent normal tissues from patients with AAA by reverse transcription
Discussion
AAA is a vascular degenerative disease with a very high morbidity rate, especially in older men with a history of smoking [30,31]. The pathogenesis of AAA is complex, with involvement of several biological progresses, such as VSMC apoptosis, inflammation, extracellular matrix degradation, proteinase activation, and increased oxidative stress [32,33]. Due to the limitation of our understanding of the molecular mechanisms of AAA progression, pharmacological treatments in clinic therapy remain
Clinical specimens
The present study was approved by the Ethics committee of Hospital of Chengdu University of Traditional Chinese Medicine. Informed written consent was obtained from each participant before tissue collection. Aortic wall biopsy specimens and adjacent normal aortic biopsy specimens were collected from 18 patients who underwent repair of AAA at Hospital of Chengdu University of Traditional Chinese Medicine from January 2017 to December 2018. All tissue samples were flash-frozen in liquid nitrogen
Funding
None.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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