Acadesine inhibits tissue factor induction and thrombus formation by activating the phosphoinositide 3-kinase/akt signaling pathway

Weiyu Zhang, Jianguo Wang, Huan Wang, Rong Tang, John D. Belcher, Benoit Viollet, Jian Guo Geng, Chunxiang Zhang, Chaodong Wu, Arne Slungaard, Chuhong Zhu, Yuqing Huo

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Objective-: Acadesine, an adenosine-regulating agent and activator of AMP-activated protein kinase, has been shown to possess antiinflammatory activity. This study investigated whether and how acadesine inhibits tissue factor (TF) expression and thrombus formation.Methods and results-: Human umbilical vein endothelial cells and human peripheral blood monocytes were stimulated with lipopolysaccharide to induce TF expression. Pretreatment with acadesine dramatically suppressed the clotting activity and expression of TF (protein and mRNA). These inhibitory effects of acadesine were unchanged for endothelial cells treated with ZM241385 (a specific adenosine A2A receptor antagonist) or AMP-activated protein kinase inhibitor compound C, and in macrophages lacking adenosine A2A receptor or α1-AMP-activated protein kinase. In endothelial cells and macrophages, acadesine activated the phosphoinositide 3-kinase/Akt signaling pathway, reduced the activity of mitogen-activated protein kinases, and consequently suppressed TF expression by inhibiting the activator protein-1 and NF-κB pathways. In mice, acadesine suppressed lipopolysaccharide-mediated increases in blood coagulation, decreased TF expression in atherosclerotic lesions, and reduced deep vein thrombus formation. Conclusion-: Acadesine inhibits TF expression and thrombus formation by activating the phosphoinositide 3-kinase/Akt pathway. This novel finding implicates acadesine as a potentially useful treatment for many disorders associated with thrombotic pathology, such as angina pain, deep vein thrombosis, and sepsis.

Original languageEnglish (US)
Pages (from-to)1000-1006
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number5
DOIs
StatePublished - May 1 2010
Externally publishedYes

Keywords

  • Anticoagulants
  • Atherosclerosis
  • Thrombus
  • Tissue factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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