MicroRNA-16 的过表达通过抑制炎症通路缓解动脉粥样硬化。
Overexpression of MicroRNA-16 Alleviates Atherosclerosis by Inhibition of Inflammatory Pathways.
机构信息
Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China.
Department of Cardiology, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin 300121, China.
出版信息
Biomed Res Int. 2020 Jul 21;2020:8504238. doi: 10.1155/2020/8504238. eCollection 2020.
BACKGROUND
Our previous study demonstrated that the expression of miR-16 was downregulated in the cell and animal models of atherosclerosis (AS), a main contributor to coronary artery disease (CAD). Overexpression of miR-16 inhibited the formation of foam cells by exerting anti-inflammatory roles. These findings indicated miR-16 may be an anti-atherogenic and CAD miRNA. The goal of this study was to further validate the expression of miR-16 in CAD patients and explore its therapeutic roles in an AS animal model.
METHODS
A total of 40 CAD patients and 40 non-CAD people were prospectively registered in our study. The AS model was established in ApoE-/- mice fed a high-fat diet. The model mice were randomly treated with miR-16 agomiR ( = 10) or miR-negative control ( = 10). Hematoxylin-eosin staining was conducted for histopathological examination in thoracic aorta samples. ELISA and immunohistochemistry were performed to determine the expression levels of inflammatory factors (IL-6, TNF-, MCP-1, IL-1, IL-10, and TGF-). qRT-PCR and western blotting were carried out to detect the mRNA and protein expression levels of PDCD4, miR-16, and mitogen-activated protein kinase pathway-related genes.
RESULTS
Compared with the normal control, miR-16 was downregulated in the plasma and peripheral blood mononuclear cell of CAD patients, and its expression level was negatively associated with IL-6 and the severity of CAD evaluated by the Gensini score, but positively related with IL-10. Injection of miR-16 agomiR in ApoE-/- mice reduced the formation of atherosclerotic plaque and suppressed the accumulation of proinflammatory factors (IL-6, TNF-, MCP-1, and IL-1) in the plasma and tissues but promoted the secretion of anti-inflammatory factors (IL-10 and TGF-). Mechanism analysis showed overexpression of miR-16 might downregulate target mRNA PDCD4 and then activate p38 and ERK1/2, but inactivate the JNK pathway.
CONCLUSIONS
Our findings suggest miR-16 may be a potential diagnostic biomarker and therapeutic target for atherosclerotic CAD.
背景
我们之前的研究表明，miR-16 在动脉粥样硬化（AS）的细胞和动物模型中的表达下调，AS 是冠心病（CAD）的主要原因。miR-16 的过表达通过发挥抗炎作用抑制泡沫细胞的形成。这些发现表明 miR-16 可能是一种抗动脉粥样硬化和 CAD 的 miRNA。本研究的目的是进一步验证 miR-16 在 CAD 患者中的表达，并在 AS 动物模型中探索其治疗作用。
方法
前瞻性登记了 40 例 CAD 患者和 40 例非 CAD 患者。用高脂肪饮食喂养 ApoE-/- 小鼠建立 AS 模型。模型小鼠随机接受 miR-16 agomiR（=10）或 miR-负对照（=10）治疗。对胸主动脉样本进行苏木精-伊红染色进行组织病理学检查。采用 ELISA 和免疫组化法测定炎性因子（IL-6、TNF-、MCP-1、IL-1、IL-10 和 TGF-）的表达水平。通过 qRT-PCR 和 Western blot 检测 PDCD4、miR-16 和丝裂原活化蛋白激酶通路相关基因的 mRNA 和蛋白表达水平。
结果
与正常对照组相比，CAD 患者血浆和外周血单核细胞中 miR-16 下调，其表达水平与 IL-6 呈负相关，与 Gensini 评分评估的 CAD 严重程度呈负相关，但与 IL-10 呈正相关。在 ApoE-/- 小鼠中注射 miR-16 agomiR 可减少动脉粥样硬化斑块的形成，并抑制炎性因子（IL-6、TNF-、MCP-1 和 IL-1）在血浆和组织中的积累，但促进抗炎因子（IL-10 和 TGF-）的分泌。机制分析表明，miR-16 的过表达可能下调靶 mRNA PDCD4，然后激活 p38 和 ERK1/2，但使 JNK 通路失活。
结论
我们的研究结果表明，miR-16 可能是动脉粥样硬化性 CAD 的潜在诊断生物标志物和治疗靶点。
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