NRP2 promotes atherosclerosis by upregulating PARP1 expression and enhancing low shear stress-induced endothelial cell apoptosis
NRP2 promotes atherosclerosis by upregulating PARP1 expression and enhancing low shear stress-induced endothelial cell apoptosis
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DOI：
10.1096/fj.202101250rr
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发表时间：
2022-02-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Junjie
中科院分区：
文献类型：
--
作者：
Luo, Shuai;Wang, Feng;Zhang, Junjie
动脉粥样硬化相关的心血管疾病是全球死亡的主要原因，其特征在于内皮细胞功能障碍的发展、巨噬细胞对氧化低密度脂蛋白的摄取增加以及随后的动脉粥样硬化斑块的形成。局部血流模式导致不均匀的动脉粥样硬化病变分布，并且由扰动血流引起的内皮功能障碍是动脉粥样硬化发展的早期步骤。本研究旨在阐明神经纤毛蛋白2（NRP 2）在低切应力（LSS）下调节内皮细胞动脉粥样硬化蛋白表型的机制。我们观察到，NRP 2的表达显着上调LSS刺激的人脐静脉内皮细胞（HUVECs）和小鼠主动脉内皮细胞。在HUVECs中敲低NRP 2显著减轻LSS诱导的细胞凋亡。相反，NRP 2过表达对HUVEC凋亡有相反的作用。动物实验表明，NRP 2基因敲低可显著减轻Apoe（-/-）小鼠动脉粥样硬化的发展。NRP 2的敲低和过表达调控了LSS条件下PARP 1蛋白的表达，进而影响了LSS相关基因的表达。此外，上游转录因子GATA 2被发现在动脉粥样硬化的进展中调节NRP 2的表达。这些结果表明，NRP 2通过调节细胞凋亡发挥重要的促动脉粥样硬化作用，并且结果揭示NRP 2是治疗动脉粥样硬化疾病的有希望的治疗靶点。
Atherosclerosis-related cardiovascular diseases are leading causes of mortality worldwide, characterized by the development of endothelial cell dysfunction, increased oxidized low-density lipoprotein uptake by macrophages, and the ensuing formation of atherosclerotic plaque. Local blood flow patterns cause uneven atherosclerotic lesion distribution, and endothelial dysfunction caused by disturbed flow is an early step in the development of atherosclerosis. The present research aims to elucidate the mechanism underlying the regulation of Neuropilin 2 (NRP2) under low shear stress (LSS) in the atheroprone phenotype of endothelial cells. We observed that NRP2 expression was significantly upregulated in LSS-stimulated human umbilical vein endothelial cells (HUVECs) and in mouse aortic endothelial cells. Knockdown of NRP2 in HUVECs significantly ameliorated cell apoptosis induced by LSS. Conversely, overexpression of NRP2 had the opposite effect on HUVEC apoptosis. Animal experiments suggest that NRP2 knockdown markedly mitigated the development of atherosclerosis in Apoe(-/-) mice. Mechanistically, NRP2 knockdown and overexpression regulated PARP1 protein expression in the condition of LSS, which in turn affected the expression of apoptosis-related genes. Moreover, the upstream transcription factor GATA2 was found to regulate NRP2 expression in the progression of atherosclerosis. These findings suggest that NRP2 plays an essential proatherosclerotic role through the regulation of cell apoptosis, and the results reveal that NRP2 is a promising therapeutic target for the treatment of atherosclerotic disorders.