冠心病患者循环微RNA-218表达、血清PCSK9水平、炎症标志物和单核细胞亚群之间的关系：他汀类药物治疗的影响

IF 2.5 Q2 MULTIDISCIPLINARY SCIENCES

Beni-Suef University Journal of Basic and Applied Sciences Pub Date : 2024-06-06 DOI:10.1186/s43088-024-00515-8

Dina A. Desouky, Nahla A. Nosair, Dalia E. Sherif, Mohammed A. El-Magd, Mohamed K. Salama

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引用次数: 0

摘要

背景蛋白质转化酶枯草酶/kexin 9 型（PCSK9）是一种主要由肝细胞产生的酶，它能打破低密度脂蛋白受体（LDL-R）、炎症标志物[类收费受体 4（TLR4）、高迁移率组盒 1（HMGB1）、肿瘤坏死因子α（TNFα）、c 反应蛋白（CRP）]和单核细胞亚型，与冠状动脉疾病（CAD）的发病机制有关。循环中的 microRNA-218（miR-218）可通过抑制单核细胞衍生的炎性细胞因子中的 HMGB1 来缓解 CAD。在此，我们探讨了他汀类药物和非他汀类药物 CAD 患者循环 miR-218 表达与血清 PCSK9 水平、炎症标志物和单核细胞亚型之间的关联。这项研究涉及 91 名健康（对照组）和 91 名稳定的 CAD 患者，他们被细分为无他汀组（NS，n = 25）、低他汀组（LS，n = 25）和高他汀组（HS，n = 41）。通过 ELISA 检测血清中 PCSK9、TLR4、HMGB1 和 TNFα 的水平，通过流式细胞术计算单核细胞亚群[经典（CM）、中间（IM）、非经典（NC）]。结果 CAD 组的 miR-218 表达明显低于对照组，而 PCSK9、炎症标志物（HMGB1、CRP、TLR4 和 TNFα）和 IM% 的水平则明显高于对照组。在 CAD 患者中，与 NS 组相比，LS 组和 HS 组的 miR-218 表达、LDL-C 水平和炎症指标明显较低，而 PCSK9 水平则明显较高。HS 组的 miR-218 表达和炎症指标最低，PCSK9 水平最高。然而，他汀类药物组和非他汀类药物组的 IM% 没有明显变化。在三个 CAD 组中，miR-218 与 PCSK9 和炎症指标（HMGB1、CRP、TLR4 和 TNFα）呈显著负相关，而只有在 NS 组中，该表达与 CM%、IM% 和 NCM% 呈显著负相关。多变量线性回归结果表明，在全部他汀类药物（LS + HS）组中，miR-218 与五个自变量（PCSK9、HMGB1、CRP、TLR4 和 TNFα）相关；在 NS 组中，miR-218 与八个自变量（PCSK9、HMGB1、CRP、TLR4 和 TNFα、CM%、IM%、NCM%）相关。在所有其他自变量不变的情况下，miR-218 的表达与他汀类药物总剂量组的 CRP（Beta = 0.234）和 PCSK9（Beta = - 0.875）显著相关；与 LS 组的 TLR4（Beta = - 0.554）；HS 组的 HMGB1（Beta = - 0.507）；NS 组的 CRP（Beta = - 0.745）。结论他汀治疗的 CAD 患者的 miR-218 与 PCSK9、HMGB1 和 TLR4 呈独特的负相关，并随之与 CAD 进展呈负相关。因此，建议将 miR-218 的激活剂和 PCSK9、HMGB1 和 TLR4 的抑制剂与他汀类药物结合使用，以有效治疗 CAD。

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Association between circulatory microRNA-218 expression, serum PCSK9 levels, inflammatory markers, and monocyte subsets in coronary artery disease patients: impact of statin therapy

Background

Proprotein convertase subtilisin/kexin type-9 (PCSK9), an enzyme produced mainly by hepatocytes and breaks low-density lipoprotein receptor (LDL-R), inflammatory markers [toll like receptor 4 (TLR4), high mobility group box 1 (HMGB1), tumor necrosis factor alpha (TNFα), c-reactive protein (CRP)], and monocyte subtypes are associated with coronary artery disease (CAD) pathogenesis. The circulating microRNA-218 (miR-218) can relieve CAD through the suppression of HMGB1 in monocyte-derived inflammatory cytokines. Herein, we explored the association between circulatory miR-218 expression and serum levels of PCSK9, inflammatory markers, and monocyte subtypes in statin and non-statin CAD patients. This study involved 91 healthy (control) and 91 stable CAD participants which were subdivided into no-statin (NS, n = 25), low-statin (LS, n = 25), and high-statin (HS, n = 41) groups. low-density lipoprotein cholesterol (LDL-C) and CRP serum levels were calorimetrically determined. Serum levels of PCSK9, TLR4, HMGB1, and TNFα were detected by ELISA, while monocyte subsets [classical (CM), intermediate (IM), non-classical (NC)] were calculated by flow cytometry. Circulatory miR-218 expression was detected by real-time PCR.

Results

The CAD group had significantly lower miR-218 expression and significantly higher levels of PCSK9, inflammatory markers (HMGB1, CRP, TLR4, and TNFα), and IM% than the control group. Among CAD patients, LS and HS groups had significantly lower miR-218 expression, LDL-C levels, and inflammatory markers and significantly higher levels of PCSK9 than the NS group. The HS group exhibited the lowest miR-218 expression and inflammatory markers and the highest PCSK9 levels. However, there were no significant changes in IM% among statin and non-statin groups. In the three CAD groups, miR-218 showed a significantly negative correlation with PCSK9 and inflammatory markers (HMGB1, CRP, TLR4, and TNFα), while this expression exhibited a significantly negative correlation with CM%, IM%, and NCM% only in the NS group. Results of multivariable linear regression indicated a correlation between miR-218 and five independent variables (PCSK9, HMGB1, CRP, TLR4, and TNFα) in the total statin (LS + HS) group, and eight independent variables (PCSK9, HMGB1, CRP, TLR4, and TNFα, CM%, IM%, NCM%) in the NS group. Provided that all other independent variables are constant, miR-218 expression was significantly correlated to CRP (Beta = 0.234) and PCSK9 (Beta = − 0.875) in the total statin group; TLR4 (Beta = − 0.554) in the LS group; HMGB1 (Beta = − 0.507) in the HS group; and CRP (Beta = − 0.745) in the NS group.

Conclusions

Statin-treated CAD patients have a unique negative correlation between miR-218 and PCSK9, HMGB1, and TLR4, and subsequently with CAD progress. Therefore, it could be recommended to combine activators of miR-218 and inhibitors of PCSK9, HMGB1, and TLR4 with statin to efficiently treat CAD.

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来源期刊

Beni-Suef University Journal of Basic and Applied Sciences MULTIDISCIPLINARY SCIENCES-

CiteScore

2.60

自引率

0.00%

发文量

期刊介绍： Beni-Suef University Journal of Basic and Applied Sciences (BJBAS) is a peer-reviewed, open-access journal. This journal welcomes submissions of original research, literature reviews, and editorials in its respected fields of fundamental science, applied science (with a particular focus on the fields of applied nanotechnology and biotechnology), medical sciences, pharmaceutical sciences, and engineering. The multidisciplinary aspects of the journal encourage global collaboration between researchers in multiple fields and provide cross-disciplinary dissemination of findings.