剪切应力与动脉粥样硬化斑块中具有动脉粥样硬化保护作用的 KLK10 脱钩

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Atherosclerosis Pub Date : 2024-10-04 DOI:10.1016/j.atherosclerosis.2024.118622

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引用次数: 0

摘要

背景和目的生理性剪切应力通过诱导内皮细胞（EC）中的保护性分子促进血管稳态。然而，在一些心血管风险较高的人群中，生理性剪切应力却与动脉粥样硬化的进展有关。为了解决这一明显的悖论，我们假设，病变动脉可能对生理性剪切应力的保护作用反应迟钝。因此，我们比较了健康动脉和动脉粥样硬化条件下暴露于生理性剪切应力的EC的转录组。方法利用三维光片成像和计算流体动力学，我们确定了NOS3是健康和动脉粥样硬化鼠动脉中生理性剪切应力的标志物。我们对健康（C57BL/6）小鼠、轻度患病（载脂蛋白-/-正常饮食）小鼠和高度患病（载脂蛋白-/-高脂饮食）小鼠的动脉血管进行了单细胞RNA测序。结果Nos3高的EC与健康动脉中生理剪切应力的几个标记相关。对Nos3高的心肌细胞进行聚类发现了8个不同的心肌细胞亚群，它们在健康动脉和患病动脉中的比例各不相同。基因本体论术语的簇特异性嵌套功能富集显示，患病动脉中的Nos3高EC富含炎症和凋亡基因表达。这些变化伴随着几种机械感受器的变化，其中包括动脉粥样硬化保护因子 KLK10，它在健康动脉的 Nos3high EC 中富集，但在严重病变动脉中则明显减少。这揭示了剪切应力、内皮功能和心血管并发症高危人群动脉粥样硬化进展之间复杂的相互作用。

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Shear stress is uncoupled from atheroprotective KLK10 in atherosclerotic plaques

Background and aims

Physiological shear stress promotes vascular homeostasis by inducing protective molecules in endothelial cells (EC). However, physiological shear stress has been linked to atherosclerosis progression in some individuals with heightened cardiovascular risk. To address this apparent paradox, we hypothesized that diseased arteries may exhibit reduced responsiveness to the protective effects of physiological shear stress. Consequently, we compared the transcriptome of EC exposed to physiological shear stress in healthy arteries versus atherosclerotic conditions.

Methods

Employing 3D light sheet imaging and computational fluid dynamics, we identified NOS3 as a marker of physiological shear stress in both healthy and atherosclerotic murine arteries. Single-cell RNA sequencing was performed on EC from healthy (C57BL/6) mice, mildly diseased (Apoe^−/− normal diet) mice, and highly diseased (Apoe^−/− high fat diet) mice. The transcriptomes of Nos3^high cells (exposed to physiological shear stress) were compared among the groups.

Results

Nos3^high EC were associated with several markers of physiological shear stress in healthy arteries. Clustering of Nos3^high EC revealed 8 different EC subsets that varied in proportion between healthy and diseased arteries. Cluster-specific nested functional enrichment of gene ontology terms revealed that Nos3^high EC in diseased arteries were enriched for inflammatory and apoptotic gene expression. These alterations were accompanied by changes in several mechanoreceptors, including the atheroprotective factor KLK10, which was enriched in Nos3^high EC in healthy arteries but markedly reduced in severely diseased arteries.

Conclusions

Physiological shear stress is uncoupled from atheroprotective KLK10 within atherosclerotic plaques. This sheds light on the complex interplay between shear stress, endothelial function, and the progression of atherosclerosis in individuals at risk of cardiovascular complications.

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来源期刊

Atherosclerosis 医学-外周血管病

CiteScore

9.80

自引率

3.80%

发文量

1269

审稿时长

36 days

期刊介绍： Atherosclerosis has an open access mirror journal Atherosclerosis: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. Atherosclerosis brings together, from all sources, papers concerned with investigation on atherosclerosis, its risk factors and clinical manifestations. Atherosclerosis covers basic and translational, clinical and population research approaches to arterial and vascular biology and disease, as well as their risk factors including: disturbances of lipid and lipoprotein metabolism, diabetes and hypertension, thrombosis, and inflammation. The Editors are interested in original or review papers dealing with the pathogenesis, environmental, genetic and epigenetic basis, diagnosis or treatment of atherosclerosis and related diseases as well as their risk factors.