Department of Vascular Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China.
Department of Vascular Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China.
Vascul Pharmacol. 2022 Feb;142:106901. doi: 10.1016/j.vph.2021.106901. Epub 2021 Aug 6.
Abdominal aortic aneurysm (AAA), a life-threatening disease, is commonly diagnosed among people with risk factors, including increasing age, male gender, and smoking. The apoptosis of smooth muscle cells (SMCs) has been reported to disrupt the vascular structural integrity, which causes AAA. Thus, we sought to characterize the potential role of microRNA (miR)-144-3p in SMC apoptosis, and to outline the molecular mechanisms involved in this pathway. We collected pathological abdominal aortic tissues and adjacent normal aortic biopsy specimens from 18 patients undergoing AAA repair surgery. The relationship between miR-144-3p expression and SMC proliferation was assessed by transfecting mimic/inhibitor of miR-144-3p in human aortic smooth muscle cells (HASMCs). Anti-growth effect of miR-144-3p and related genes was evaluated in a murine AAA model. Dual luciferase reporter gene assay was adopted to validate the targeting relationship between miR-144-3p and enhancer of zeste homolog 2 (EZH2), and the enrichment of EZH2 in the p21 promoter region was determined by chromatin immunoprecipitation assay. MiR-144-3p was highly expressed in AAA tissues. Enhanced miR-144-3p diminished SMC proliferation by binding to the EZH2 3'-untranslated region and thereby inhibiting EZH2 expression. In addition, EZH2 was highly enriched in the promoter region of p21, and knockdown of p21 expression could rescue the effect of miR-144-3p on SMC proliferation and apoptosis. miR-144-3p serves as a promoter for the apoptosis of SMCs, which contributes to the occurrence and progression of AAA. This observation will serve as the basis for further investigations into potential p21-based therapies for AAA treatment.
腹主动脉瘤（AAA）是一种危及生命的疾病，常见于有危险因素的人群，包括年龄增长、男性和吸烟。平滑肌细胞（SMCs）的凋亡已被报道破坏了血管结构的完整性，从而导致 AAA。因此，我们试图描述 microRNA（miR）-144-3p 在 SMC 凋亡中的潜在作用，并概述涉及该途径的分子机制。我们收集了 18 名接受 AAA 修复手术的患者的病理性腹主动脉组织和相邻正常主动脉活检标本。通过转染 miR-144-3p 的模拟物/抑制剂，评估 miR-144-3p 表达与 SMC 增殖之间的关系。在小鼠 AAA 模型中评估 miR-144-3p 和相关基因的抗生长作用。采用双荧光素酶报告基因实验验证 miR-144-3p 与增强子的 zeste 同源物 2（EZH2）之间的靶向关系，并通过染色质免疫沉淀实验确定 EZH2 在 p21 启动子区域的富集。miR-144-3p 在 AAA 组织中高表达。增强的 miR-144-3p 通过结合 EZH2 的 3'-非翻译区并抑制 EZH2 表达，从而减少 SMC 的增殖。此外，EZH2 在 p21 的启动子区域高度富集，并且敲低 p21 表达可以挽救 miR-144-3p 对 SMC 增殖和凋亡的影响。miR-144-3p 作为 SMC 凋亡的启动子，有助于 AAA 的发生和发展。这一观察结果将为进一步研究基于 p21 的 AAA 治疗的潜在疗法提供依据。
