Macrophage activation by heparanase is mediated by TLR-2 and TLR-4 and associates with plaque progression

Miry Blich*, Amnon Golan, Gil Arvatz, Anat Sebbag, Itay Shafat, Edmond Sabo, Victoria Cohen-Kaplan, Sirouch Petcherski, Shani Avniel-Polak, Amnon Eitan, Haim Hammerman, Doron Aronson, Elena Axelman, Neta Ilan, Gabriel Nussbaum, Israel Vlodavsky

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Objective-: Factors and mechanisms that activate macrophages in atherosclerotic plaques are incompletely understood. We examined the capacity of heparanase to activate macrophages. METHODS AND RESULTS-: Highly purified heparanase was added to mouse peritoneal macrophages and macrophage-like J774 cells, and the levels of tumor necrosis factor-α, matrix metalloproteinase-9, interlukin-1, and monocyte chemotactic protein-1 were evaluated by ELISA. Gene expression was determined by RT-PCR. Cells collected from Toll-like receptor-2 and Toll-like receptor-4 knockout mice were evaluated similarly. Heparanase levels in the plasma of patients with acute myocardial infarction, stable angina, and healthy subjects were determined by ELISA. Immunohistochemistry was applied to detect the expression of heparanase in control specimens and specimens of patients with stable angina or acute myocardial infarction. Addition or overexpression of heparanase variants resulted in marked increase in tumor necrosis factor-α, matrix metalloproteinase-9, interlukin-1, and monocyte chemotactic protein-1 levels. Mouse peritoneal macrophages harvested from Toll-like receptor-2 or Toll-like receptor-4 knockout mice were not activated by heparanase. Plasma heparanase level was higher in patients with acute myocardial infarction, compared with patients with stable angina and healthy subjects. Pathologic coronary specimens obtained from vulnerable plaques showed increased heparanase staining compared with specimens of stable plaque and controls. CONCLUSION-: Heparanase activates macrophages, resulting in marked induction of cytokine expression associated with plaque progression toward vulnerability.

Original languageAmerican English
Pages (from-to)e56-e65
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • TLR
  • TNFα
  • heparanase
  • macrophages
  • vulnerable plaque

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