平滑肌细胞中赖氨酸氧化酶的表达决定了高胆固醇血症诱发的动脉粥样硬化的内膜钙化水平。

IF 1.9 Q3 PERIPHERAL VASCULAR DISEASE
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引用次数: 0

摘要

介绍:心血管钙化是一个重要的公共卫生问题,但治疗需求尚未得到满足。我们之前已经证明,赖氨酰氧化酶(LOX)活性通过影响细胞外基质重塑,对血管壁平滑肌细胞(VSMCs)和瓣膜间质细胞(VICs)的钙化产生关键影响。我们对 LOX 参与动脉粥样硬化和血管钙化以及主动脉瓣矿化的情况进行了深入研究:方法:我们在人类动脉粥样硬化病变和实验模型、主动脉瓣狭窄患者的瓣膜、VIC 以及在 CMLV 中过表达 LOX 的转基因小鼠模型(TgLOXCMLV)中进行了免疫组化和表达研究。通过给小鼠注射编码 PCSK9 突变形式的腺相关病毒(AAV-PCSK9D374Y)并结合致动脉粥样硬化饮食,诱导小鼠出现高脂血症和动脉粥样硬化:结果:在用 PCSK9D374Y 转导的对照组(C57BL/6J)动物的肱动脉和载脂蛋白E-/-小鼠的主动脉根部形成的动脉粥样硬化病变的新内膜层和血管内皮细胞丰富的区域,LOX 的表达都有所增加。在 TgLOXCMLV 小鼠中,PCSK9D374Y 转导并未显著改变基质重塑、炎症、氧化应激和成骨细胞分化相关基因在主动脉中的表达。同样,LOX 转基因也不会改变主动脉弓、肱动脉和主动脉根部动脉粥样硬化病变的大小或脂质含量,但会加剧钙化。在赖氨酰氧化酶同工酶中,LOX是高度钙化的人体瓣膜中表达最多的同工酶家族成员,与RUNX2共聚焦于VICs中。核受体 NOR-1 在 VIC 中的过量表达导致钙沉积减少和 RUNX2 水平降低,这与 LOX 的减少有关:我们的研究结果表明,LOX 在动脉粥样硬化病变中表达增加,这种酶在 VSMC 中的过表达不会影响动脉粥样斑块的大小或其脂质含量,但会影响其钙化程度。此外,这些数据还表明,NOR-1 在血管内皮细胞中驱动的钙化减少将涉及 LOX 的减少。这些证据支持将 LOX 作为心血管钙化的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
La expresión de la lisil oxidasa en las células musculares lisas determina el nivel de calcificación de la íntima en la aterosclerosis inducida por hipercolesterolemia

Introduction

Cardiovascular calcification is an important public health issue with an unmeet therapeutic need. We had previously shown that lysyl oxidase (LOX) activity critically influences vascular wall smooth muscle cells (VSMCs) and valvular interstitial cells (VICs) calcification by affecting extracellular matrix remodeling. We have delved into the participation of LOX in atherosclerosis and vascular calcification, as well as in the mineralization of the aortic valve.

Methods

Immunohistochemical and expression studies were carried out in human atherosclerotic lesions and experimental models, valves from patients with aortic stenosis, VICs, and in a genetically modified mouse model that overexpresses LOX in CMLV (TgLOXCMLV). Hyperlipemia and atherosclerosis was induced in mice through the administration of adeno-associated viruses encoding a PCSK9 mutated form (AAV-PCSK9D374Y) combined with an atherogenic diet.

Results

LOX expression is increased in the neointimal layer of atherosclerotic lesions from human coronary arteries and in VSMC-rich regions of atheromas developed both in the brachiocephalic artery of control (C57BL/6J) animals transduced with PCSK9D374Y and in the aortic root of ApoE−/− mice. In TgLOXCMLV mice, PCSK9D374Y transduction did not significantly alter the enhanced aortic expression of genes involved in matrix remodeling, inflammation, oxidative stress and osteoblastic differentiation. Likewise, LOX transgenesis did not alter the size or lipid content of atherosclerotic lesions in the aortic arch, brachiocephalic artery and aortic root, but exacerbated calcification. Among lysyl oxidase isoenzymes, LOX is the most expressed member of this family in highly calcified human valves, colocalizing with RUNX2 in VICs. The lower calcium deposition and decreased RUNX2 levels triggered by the overexpression of the nuclear receptor NOR-1 in VICs was associated with a reduction in LOX.

Conclusions

Our results show that LOX expression is increased in atherosclerotic lesions, and that overexpression of this enzyme in VSMC does not affect the size of the atheroma or its lipid content, but it does affect its degree of calcification. Further, these data suggest that the decrease in calcification driven by NOR-1 in VICs would involve a reduction in LOX. These evidences support the interest of LOX as a therapeutic target in cardiovascular calcification.

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来源期刊
Clinica e Investigacion en Arteriosclerosis
Clinica e Investigacion en Arteriosclerosis PERIPHERAL VASCULAR DISEASE-
CiteScore
3.20
自引率
6.20%
发文量
44
审稿时长
40 days
期刊介绍: La publicación idónea para acceder tanto a los últimos originales de investigación como a formación médica continuada sobre la arteriosclerosis y su etiología, epidemiología, fisiopatología, diagnóstico y tratamiento. Además, es la publicación oficial de la Sociedad Española de Arteriosclerosis.
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