患者源性内皮祖细胞中髓过氧化物酶的表达：与冠状动脉疾病及线粒体功能的关系。

Expression of Myeloperoxidase in Patient-Derived Endothelial Colony-Forming Cells-Associations with Coronary Artery Disease and Mitochondrial Function.

机构信息

Kolling Institute, 10 Westbourne Street, St Leonards, Sydney, NSW 2064, Australia.

The Victorian Heart Institute and Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, Melbourne, VIC 3800, Australia.

出版信息

Biomolecules. 2024 Oct 16;14(10):1308. doi: 10.3390/biom14101308.

DOI:10.3390/biom14101308

PMID:39456241

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11505856/

Abstract

BACKGROUND AND AIMS

Myeloperoxidase (MPO) plays a critical role in the innate immune response and has been suggested to be a surrogate marker of oxidative stress and inflammation, with elevated levels implicated in cardiovascular diseases, such as atherosclerosis and heart failure, as well as in conditions like rheumatoid arthritis and cancer. While MPO is well-known in leukocytes, its expression and function in human endothelial cells remain unclear. This study investigates MPO expression in patient-derived endothelial colony-forming cells (ECFCs) and its potential association with CAD and mitochondrial function.

METHODS

ECFCs were cultured from the peripheral blood of 93 BioHEART-CT patients. MPO expression and associated functions were examined using qRT-PCR, immunochemistry, flow cytometry, and MPO activity assays. CAD presence was defined using CT coronary angiography (CACS > 0).

RESULTS

We report MPO presence in patient-derived ECFCs for the first time. MPO protein expression occurred in 70.7% of samples ( = 41) which had nuclear co-localisation, an atypical observation given its conventional localisation in the granules of neutrophils and monocytes. This suggests potential alternative roles for MPO in nuclear processes. MPO mRNA expression was detected in 66.23% of samples ( = 77). CAD patients had a lower proportion of MPO-positive ECFCs compared to non-CAD controls (57.45% vs. 80%, = 0.04), a difference that persisted in the statin-naïve sub-cohort (53.85% vs. 84.62%, = 0.02). Non-CAD patients with MPO expression showed upregulated mitochondrial-antioxidant genes (, , , , ). In contrast, CAD patients with MPO gene expression had heightened mROS production and mitochondrial mass and decreased mitochondrial function compared to that of CAD patients without MPO gene expression.

CONCLUSIONS

MPO is present in the nucleus of ECFCs. In non-CAD ECFCs, MPO expression is linked to upregulated mitochondrial-antioxidant genes, whereas in CAD ECFCs, it is associated with greater mitochondrial dysfunction.

摘要

背景与目的

髓过氧化物酶（MPO）在先天免疫反应中起着关键作用，并且被认为是氧化应激和炎症的替代标志物，其水平升高与心血管疾病（如动脉粥样硬化和心力衰竭）以及类风湿关节炎和癌症等疾病有关。虽然 MPO 在白细胞中广为人知，但它在人内皮细胞中的表达和功能仍不清楚。本研究调查了 MPO 在患者来源的内皮细胞形成细胞（ECFCs）中的表达及其与 CAD 和线粒体功能的潜在关联。

方法

从 93 名 BioHEART-CT 患者的外周血中培养 ECFCs。使用 qRT-PCR、免疫化学、流式细胞术和 MPO 活性测定法检查 MPO 的表达和相关功能。使用 CT 冠状动脉造影（CACS>0）定义 CAD 的存在。

结果

我们首次报告了患者来源的 ECFCs 中存在 MPO。MPO 蛋白表达发生在 70.7%的样本（=41）中，这些样本具有核共定位，这是一种不寻常的观察结果，因为其传统定位在中性粒细胞和单核细胞的颗粒中。这表明 MPO 在核过程中可能具有替代作用。在 66.23%的样本（=77）中检测到 MPO mRNA 表达。与非 CAD 对照组相比，CAD 患者的 MPO 阳性 ECFCs 比例较低（57.45%对 80%，=0.04），在他汀类药物初治亚组中这种差异仍然存在（53.85%对 84.62%，=0.02）。表达 MPO 的非 CAD 患者表现出上调的线粒体抗氧化基因（、、、、）。相比之下，与非 CAD 患者相比，CAD 患者中具有 MPO 基因表达的患者表现出更高的 mROS 产生、线粒体质量和降低的线粒体功能。