Up-regulation of endothelial monocyte chemoattractant protein-1 by coplanar PCB77 is caveolin-1-dependent

Zuzana Majkova, Eric Smart, Michal Toborek, Bernhard Hennig

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Atherosclerosis, the primary cause of heart disease and stroke is initiated in the vascular endothelium, and risk factors for its development include environmental exposure to persistent organic pollutants. Caveolae are membrane microdomains involved in regulation of many signaling pathways, and in particular in endothelial cells. We tested the hypothesis that intact caveolae are required for coplanar PCB77-induced up-regulation of monocyte chemoattractant protein-1 (MCP-1), an endothelium-derived chemokine that attracts monocytes into sub-endothelial space in early stages of the atherosclerosis development. Atherosclerosis-prone LDL-R-/- mice (control) or caveolin-1-/-/LDL-R-/- mice were treated with PCB77. PCB77 induced aortic mRNA expression and plasma protein levels of MCP-1 in control, but not caveolin-1-/-/LDL-R-/- mice. To study the mechanism of this effect, primary endothelial cells were used. PCB77 increased MCP-1 levels in endothelial cells in a time- and concentration-dependent manner. This effect was abolished by caveolin-1 silencing using siRNA. Also, MCP-1 up-regulation by PCB77 was prevented by inhibiting p38 and c-Jun N-terminal kinase (JNK), but not ERK1/2, suggesting regulatory functions via p38 and JNK MAPK pathways. Finally, pre-treatment of endothelial cells with the aryl hydrocarbon receptor (AhR) inhibitor α-naphthoflavone (α-NF) partially blocked MCP-1 up-regulation. Thus, our data demonstrate that coplanar PCB77 can induce MCP-1 expression by endothelial cells and that this effect is mediated by AhR, as well as p 38 and JNK MAPK pathways. Intact caveolae are required for these processes both in vivo and in vitro. This further supports a key role for caveolae in vascular inflammation induced by persistent organic pollutants.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalToxicology and Applied Pharmacology
Volume237
Issue number1
DOIs
StatePublished - May 15 2009

Keywords

  • 3,3′,4,4′-tetrachlorobiphenyl (PCB77)
  • Caveolin-1
  • Endothelial cells
  • Monocyte chemoattractant protein (MCP-1)

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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