Lipocalin-2 exerts pro-atherosclerotic effects as evidenced by in vitro and in vivo experiments | springermedizin.de

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Heart and Vessels

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01.07.2020 | Original Article

Lipocalin-2 exerts pro-atherosclerotic effects as evidenced by in vitro and in vivo experiments

verfasst von: Koichiro Shibata, Kengo Sato, Remina Shirai, Tomomi Seki, Taisuke Okano, Tomoyuki Yamashita, Ayaka Koide, Mutsumi Mitsuboshi, Yusaku Mori, Tsutomu Hirano, Takuya Watanabe

Erschienen in: Heart and Vessels | Ausgabe 7/2020

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Abstract

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.

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Titel: Lipocalin-2 exerts pro-atherosclerotic effects as evidenced by in vitro and in vivo experiments
verfasst von: Koichiro Shibata
Kengo Sato
Remina Shirai
Tomomi Seki
Taisuke Okano
Tomoyuki Yamashita
Ayaka Koide
Mutsumi Mitsuboshi
Yusaku Mori
Tsutomu Hirano
Takuya Watanabe
Publikationsdatum: 01.07.2020
Verlag: Springer Japan
Erschienen in: Heart and Vessels / Ausgabe 7/2020
Print ISSN: 0910-8327
Elektronische ISSN: 1615-2573
DOI: https://doi.org/10.1007/s00380-020-01556-6

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