Abstract：
Natriuretic peptide receptor 1 (NPR1) serves as a modulator of vascular endothelial homeostasis. Interactions between monocytes and endothelial cells may initiate endothelium dysfunction, which is known as an early hallmark of atherosclerosis. In this study, we performed RNA-sequencing analysis for the aorta of Npr1 knockout (Npr1+/-) mice and found that differentially expressed genes were significantly related to cell adhesion. This result was supported by an increased expression of intercellular adhesion molecule 1 (ICAM-1) in the aortic endothelium of Npr1+/- mice. Moreover, we observed that the knockdown of NPR1 increased ICAM-1 expression and promoted THP-1 monocyte adhesion to human umbilical vein endothelial cells (HUVECs). NPR1 overexpression decreased ICAM-1 expression and inhibited the adhesion of monocytes to HUVECs treated by TNF-α (a cell adhesion inducer). Further analysis showed that adhesion-related genes were enriched in the focal adhesion signaling pathway, in which integrin beta 4 (Itgb4) was determined as a key gene. Notably, ITGB4 expression increased in vascular endothelium of Npr1+/- mice and in NPR1-knockdown HUVECs. The deficiency of ITGB4 decreased ICAM-1 expression and attenuated monocyte adhesion to NPR1-knockdown endothelial cells. Additionally, a reduced NPR1 and an increased ITGB4 expression level were found in an atherosclerosis mouse model. In conclusion, our findings demonstrate that NPR1 deficiency increases vascular endothelial cell adhesion by stimulating ITGB4 expression, which may contribute to the development of atherosclerosis.
摘要：
利钠肽受体1（NPR1）可作为血管内皮稳态的调节剂。单核细胞和内皮细胞之间的相互作用可能引发内皮功能障碍，这被称为动脉粥样硬化的早期标志。在这项研究中,我们对Npr1敲除(Npr1+/-)小鼠的主动脉进行RNA测序分析,发现差异表达基因与细胞粘附显著相关.该结果得到Npr1+/-小鼠主动脉内皮中细胞间粘附分子1(ICAM-1)表达增加的支持。此外，我们观察到NPR1的敲低增加了ICAM-1的表达，并促进了THP-1单核细胞与人脐静脉内皮细胞（HUVECs）的粘附。NPR1过表达降低了ICAM-1的表达，并抑制了单核细胞与TNF-α（细胞粘附诱导剂）处理的HUVEC的粘附。进一步分析表明,粘着相关基因富集在粘着斑信号通路,其中整合素β4(Itgb4)被确定为关键基因。值得注意的是,ITGB4在Npr1+/-小鼠的血管内皮和NPR1敲低的HUVEC中表达增加。ITGB4的缺乏降低了ICAM-1的表达并减弱了单核细胞与NPR1敲低的内皮细胞的粘附。此外,在动脉粥样硬化小鼠模型中发现NPR1降低和ITGB4表达水平升高.总之,我们的研究结果表明，NPR1缺乏通过刺激ITGB4表达增加血管内皮细胞粘附，这可能有助于动脉粥样硬化的发展。
