Shibata Koichiro, Sato Kengo, Shirai Remina, Seki Tomomi, Okano Taisuke, Yamashita Tomoyuki, Koide Ayaka, Mitsuboshi Mutsumi, Mori Yusaku, Hirano Tsutomu, Watanabe Takuya
Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-City, Tokyo, 192-0392, Japan.
Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Heart Vessels. 2020 Jul;35(7):1012-1024. doi: 10.1007/s00380-020-01556-6. Epub 2020 Jan 20.
Lipocalin-2 (LCN2), a multiple bioactive hormone particularly expressed in adipose tissue, neutrophils, and macrophages, is known to exhibit anti-microbial effect, increase inflammatory cytokine levels, and maintain glucose homeostasis. Serum LCN2 level is positively correlated with the severity of coronary artery disease. However, it still remains unknown whether LCN2 affects atherogenesis. We assessed the effects of LCN2 on the inflammatory response and monocyte adhesion in human umbilical vein endothelial cells (HUVECs), inflammatory phenotype and foam cell formation in THP1 monocyte-derived macrophages, and migration and proliferation of human aortic smooth muscle cells (HASMCs) in vitro and aortic lesions in Apoe mice in vivo. LCN2 and its receptor, low-density lipoprotein (LDL)-related protein-2, were expressed in THP1 monocytes, macrophages, HASMCs, and HUVECs. LCN2 significantly enhanced THP1 monocyte adhesion to HUVECs accompanied with upregulation of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin associated with nuclear factor-κB (NF-κB) upregulation in HUVECs. LCN2 significantly increased HUVEC proliferation and oxidized LDL-induced foam cell formation in THP1 monocyte-derived macrophages. LCN2 significantly increased the inflammatory M1 phenotype associated with NF-κB upregulation during differentiation of THP1 monocytes into macrophages. In HASMCs, LCN2 significantly promoted the migration and collagen-1 expression without inducing proliferation, which are associated with increased protein expression of phosphoinositide 3-kinase and phosphorylation of Akt, extracellular signal-regulated kinase, c-jun-N-terminal kinase, and NF-κB. Chronic LCN2 infusion into Apoe mice significantly accelerated the development of aortic atherosclerotic lesions, with increased intraplaque monocyte/macrophage infiltration and pentraxin-3 and collagen-1 expressions. Our results suggested that LCN2 accelerates the development of atherosclerosis. Thus, LCN2 could serve as a novel therapeutic target for atherosclerotic diseases.
脂质运载蛋白-2（LCN2）是一种多种生物活性激素，尤其在脂肪组织、中性粒细胞和巨噬细胞中表达，已知其具有抗菌作用、可提高炎症细胞因子水平并维持葡萄糖稳态。血清LCN2水平与冠状动脉疾病的严重程度呈正相关。然而，LCN2是否影响动脉粥样硬化的发生仍不清楚。我们评估了LCN2对人脐静脉内皮细胞（HUVECs）炎症反应和单核细胞黏附、THP1单核细胞衍生巨噬细胞的炎症表型和泡沫细胞形成、人主动脉平滑肌细胞（HASMCs）体外迁移和增殖以及载脂蛋白E（Apoe）小鼠体内主动脉病变的影响。LCN2及其受体低密度脂蛋白（LDL）相关蛋白-2在THP1单核细胞、巨噬细胞、HASMCs和HUVECs中表达。LCN2显著增强THP1单核细胞与HUVECs的黏附，同时上调HUVECs中细胞间黏附分子-1、血管细胞黏附分子-1和E-选择素，并与核因子-κB（NF-κB）上调相关。LCN2显著增加HUVECs增殖以及THP1单核细胞衍生巨噬细胞中氧化型低密度脂蛋白诱导的泡沫细胞形成。LCN2显著增加THP1单核细胞分化为巨噬细胞过程中与NF-κB上调相关的炎症M1表型。在HASMCs中，LCN2显著促进迁移和胶原蛋白-1表达，但不诱导增殖，这与磷酸肌醇3激酶蛋白表达增加以及Akt、细胞外信号调节激酶、c-jun氨基末端激酶和NF-κB的磷酸化有关。向Apoe小鼠长期输注LCN2显著加速主动脉粥样硬化病变的发展，斑块内单核细胞/巨噬细胞浸润增加，血清淀粉样蛋白P成分（pentraxin-3）和胶原蛋白-1表达增加。我们的结果表明，LCN2加速动脉粥样硬化的发展。因此，LCN2可作为动脉粥样硬化疾病的一个新的治疗靶点。
