Research Paper Volume 13, Issue 10 pp 13859—13875

Curcumin inhibits the proliferation and migration of vascular smooth muscle cells by targeting the chemerin / CMKLR1 / LCN2 axis

Yaqiong He1, *, , Rongning Wang1, *, , Peng Zhang1, , Jianlong Yan1, , Nan Gong1, , Yuhang Li2, , Shaohong Dong1, ,

  • 1 Department of Cardiology, Shenzhen People’s Hospital, Jinan University, Shenzhen 518000, Guangdong, China
  • 2 Department of Orthopedics, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong, China
* Equal contribution

Received: February 3, 2020       Accepted: January 20, 2021       Published: May 24, 2021      

https://doi.org/10.18632/aging.202980
How to Cite

Copyright: © 2021 He et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Atherosclerosis (AS) is a chronic progressive inflammatory disease and a leading cause of death worldwide. Being a novel adipokine, chemerin is reported to be positively correlated with the severity of AS, yet its underlying mechanisms in AS remains elusive. It is well-known that AS development is significantly attributed to abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, we investigated the role of the chemerin / chemokine-like receptor 1 (CMKLR1, chemerin receptor) signaling, and the potential therapeutic effect of curcumin in VSMCs proliferation and migration during AS by establishing a high fat diet (HFD) mouse model. We found that CMKLR1 was highly expressed in HFD-induced AS tissues and that its expression level was positively correlated with aortic proliferation. Knockdown of CMKLR1 significantly inhibited VSMCs proliferation and migration, as evidenced by the EdU-incorporation assay, wound healing assay, and the induction of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-9 (MMP-9) expression. Furthermore, we discovered that Lipocalin-2 (LCN2) acts as a key factor involved in CMKLR1-mediated VSMCs proliferation and migration via the p38 / MAPK and Wnt / β-catenin signaling pathways, and we demonstrated that curcumin inhibits VSMCs proliferation and migration by inhibiting chemerin / CMKLR1 / LCN2, thereby reducing AS progression. Our findings suggest that chemerin / CMKLR1 activation promotes the development of AS; hence, targeting the chemerin / CMKLR1 / LCN2 signaling pathway may be a reasonable treatment modality for AS.

Abbreviations

AS: atherosclerosis; VSMC: vascular smooth muscle cell; CMKLR1: chemokine-like receptor 1; HFD: high fat diet; PCNA: proliferating cell nuclear antigen; MMP-9: matrix metalloproteinase-9; LCN2: Lipocalin-2; RARRES2: retinoic acid receptor response protein 2; Tig2: tazarotene-induced gene 2 protein; ApoE−/−: apo-lipoprotein E−/−; NP: natural product; IHC: immunohistochemistry; EdU: 5-Ethynyl-2'-deoxyuridine; PBS: phosphate-buffered saline; DMEM: dulbecco's modified eagle's medium; DMSO: dimethyl sulfoxide; BSA: bovine serum albumin; siRNA: small interfering RNA; CCK8: cell counting kit-8; NC: negative control; SD: standard deviation; SC: scramble control; n.s.: no significant.