Zedoarondiol inhibits atherosclerosis by regulating monocyte migration and adhesion via CXCL12/CXCR4 pathway

Pharmacol Res. 2022 Aug;182:106328. doi: 10.1016/j.phrs.2022.106328. Epub 2022 Jun 27.

Abstract

Atherosclerosis (AS) is an essential pathological changes of ischemic cardio-cerebrovascular disease, and monocyte migration and adhesion to endothelial cells are the critical pathological process in AS. Our previous studies demonstrated a beneficial effect of zedoarondiol in AS, but whether the mechanism is associated with monocyte migration and adhesion to endothelial cells remains unclear. In this study, we investigated whether the anti-atherosclerotic effects of zedoarondiol were associated with decreasing migration and adhesion of monocytes. The oil red O staining demonstrated that zedoarondiol ameliorated AS plaques in en face aorta and aortic root of apolipoprotein E gene knocked (apoE-/-) mice. In vitro, zedoarondiol decreased human monocytic macrophage-like cell line (THP-1) monocytes migration and adhesion to endothelial cells. Single-cell RNA sequencing analysis (scRNA-seq) in mice indicated that zedoarondiol decreased monocytes adhesion to endothelial cells by regulating CXC chemokine ligand 12/CXC chemokine receptor 4 (CXCL12/CXCR4) pathway, which was verified by Western blot of THP-1 monocytes;zedoarondiol also decreased the expressions of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and nuclear factor-kappa B (NF/κB), the downstream proteins of CXCL12/CXCR4 pathway. In conclusion, zedoarondiol ameliorated AS plaque and inhibited monocyte migration and adhesion to endothelial cells via regulating CXCL12/CXCR4 pathway, suggesting that zedoarondiol might be a new promising drug for AS.

Keywords: Adhesion; Atherosclerosis; Migration; Monocyte; Single-cell RNA sequencing; Zedoarondiol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis* / metabolism
  • Cell Adhesion
  • Chemokine CXCL12 / metabolism
  • Endothelial Cells / metabolism
  • Humans
  • Lactones
  • Mice
  • Monocytes / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plaque, Atherosclerotic* / drug therapy
  • Plaque, Atherosclerotic* / metabolism
  • Receptors, CXCR4 / metabolism
  • Sesquiterpenes

Substances

  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Lactones
  • Receptors, CXCR4
  • Sesquiterpenes
  • zedoarondiol