Receptor activator of nuclear factor κb ligand is a novel inducer of tissue factor in macrophages

Jihye Kim, Jeong Ki Min, Jeong Ae Park, Hyun Ju Doh, Yeon Sook Choi, Jaerang Rho, Young Myeong Kim, Young Guen Kwon

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Rationale: Although recent studies have suggested a role for the receptor activator of nuclear factor κB ligand (RANKL) in the late stages of atherosclerosis (eg, plaque destabilization and rupture), the underlying mechanisms and subsequent events are unclear. Objective: Because blood clotting is common after plaque rupture, we hypothesized that RANKL influenced tissue factor (TF) expression and activity to initiate the coagulation cascade. Methods and Results: RANKL increased the TF mRNA level and procoagulant activity in macrophages, as determined by semiquantitative reverse transcription polymerase chain reaction (semiquantitative RT-PCR) and a chromogenic assay. TF promoter analysis revealed that AP-1 and Egr-1 are responsible for RANKL-induced TF transcription. In addition, RANKL increased phosphorylation of c-Jun NH 2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2. RANKL-induced TF expression was attenuated by JNK- and MEK1-specific inhibitors and by small interfering RNA knockdown of c-Jun and Egr-1. Conclusion: Our results indicate that RANKL induces TF in macrophages mainly through the cooperative action of AP-1 and Egr-1 via JNK and ERK1/2 pathways. These findings provide strong mechanistic support for the role of RANKL in the thrombogenicity of atherosclerotic plaques.

Original languageEnglish
Pages (from-to)871-876
Number of pages6
JournalCirculation Research
Volume107
Issue number7
DOIs
Publication statusPublished - 2010 Oct 1

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

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