高密度脂蛋白胆固醇相关的基因表达变化揭示了高密度脂蛋白在冠心病中的促动脉粥样硬化和动脉保护作用。

HDL Cholesterol-Associated Shifts in the Expression of Preselected Genes Reveal both Pro-Atherogenic and Atheroprotective Effects of HDL in Coronary Artery Disease.

机构信息

Laboratory of Structural Fundamentals of Lipoprotein Metabolism, National Medical Research Center for Therapy and Preventive Medicine, 101990 Moscow, Russia.

Laboratory of Human Molecular Genetics, National Research Center "Kurchatov Institute", 123182 Moscow, Russia.

出版信息

Front Biosci (Landmark Ed). 2024 Nov 21;29(11):396. doi: 10.31083/j.fbl2911396.

DOI:10.31083/j.fbl2911396

PMID:39614436

Abstract

BACKGROUND

The associations of high-density lipoprotein (HDL) level and functionality with lipid metabolism, inflammation, and innate immunity in coronary artery disease (CAD) remain controversial. The differential expression of a set of genes related to HDL metabolism (24 genes) and atherogenesis (41 genes) in peripheral blood mononuclear cells (PBMC) from CAD and control patients with varied HDL cholesterol (HDL-C) levels was compared.

METHODS

76 male patients 40-60 years old with CAD diagnosed by angiography and 63 control patients were divided into three groups with low, normal (1.0-1.4 mM), and increased HDL-C levels. Transcript levels were measured by real-time PCR. The differentially expressed genes (DEGs) and associated metabolic pathways were analyzed for three groups, with prevalent CAD as an outcome.

RESULTS

The common feature was the increased odds ratio values for liver X receptor (LXR) gene expression for three patient groups. CAD patients with low HDL-C possessed 24 DEGs with lower expression of genes involved in cholesterol efflux, and down-regulated and are suggested as gene signatures. CAD patients with normal HDL-C possessed nine DEGs with down-regulated and as gene signatures. CAD patients with increased HDL-C possessed 19 DEGs with down-regulated and as gene signatures. With gene expression signatures, one standard deviation higher average gene expressions were associated with 5.1-, 48.8-, and 38.9-fold fewer CAD cases for three patient groups. As HDL-C increased in CAD patients, the expression of , , and genes increased, while the expression of and genes, involved in cholesterol synthesis and trafficking, decreased. The expression of , , , , , , , and genes, involved in angiogenesis and inflammation mainly via nuclear factor-κB (NF-κB), decreased.

CONCLUSIONS

The increased accumulation of cholesteryl ester in PBMC from patients with low HDL-C was suggested. This assumption contrasts with the suggested accumulation of free cholesterol in PBMC from patients with increased HDL-C, concomitant with suppression of cholesterol synthesis and traffic to the plasma membrane, and with an inflammatory state controlled by depressed CD36-mediated and upregulated apoE-mediated immunometabolic signaling. Gene signatures may be used for the diagnosis, prognosis, and treatment of CAD in dependence on HDL-C levels.

摘要

背景

高密度脂蛋白（HDL）水平和功能与冠心病（CAD）中的脂质代谢、炎症和先天免疫的关联仍存在争议。比较了不同 HDL 胆固醇（HDL-C）水平的 CAD 患者和对照患者外周血单核细胞（PBMC）中一组与 HDL 代谢（24 个基因）和动脉粥样硬化（41 个基因）相关的基因的差异表达。

方法

76 名年龄在 40-60 岁的男性 CAD 患者经血管造影诊断，63 名对照患者分为低、正常（1.0-1.4mM）和升高的 HDL-C 水平三组。通过实时 PCR 测量转录水平。以常见 CAD 为结果，分析三组的差异表达基因（DEGs）和相关代谢途径。

结果

共同的特征是三个患者组的肝 X 受体（LXR）基因表达的优势比增加。低 HDL-C 的 CAD 患者具有 24 个 DEG，胆固醇流出相关基因表达降低，下调的和被认为是基因特征。正常 HDL-C 的 CAD 患者具有 9 个 DEG，下调的和被认为是基因特征。升高的 HDL-C 的 CAD 患者具有 19 个 DEG，下调的和被认为是基因特征。使用基因表达特征，三个患者组中平均基因表达高出一个标准差与 CAD 病例减少 5.1、48.8 和 38.9 倍相关。随着 CAD 患者 HDL-C 的增加，、、和基因的表达增加，而胆固醇合成和转运相关的、基因的表达减少。主要通过核因子-κB（NF-κB）参与血管生成和炎症的、、、、、和基因的表达减少。

结论

低 HDL-C 的患者的 PBMC 中胆固醇酯的积累增加。这种假设与升高的 HDL-C 的患者的 PBMC 中游离胆固醇的积累形成对比，同时伴随着胆固醇合成和向质膜转运的抑制，以及 CD36 介导的和上调的 apoE 介导的免疫代谢信号的抑制。基因特征可用于依赖 HDL-C 水平的 CAD 的诊断、预后和治疗。