Acadesine Inhibits Tissue Factor Induction and Thrombus Formation by Activating the Phosphoinositide 3-Kinase/Akt Signaling Pathway

Author:

Zhang Weiyu1,Wang Jianguo1,Wang Huan1,Tang Rong1,Belcher John D.1,Viollet Benoit1,Geng Jian-Guo1,Zhang Chunxiang1,Wu Chaodong1,Slungaard Arne1,Zhu Chuhong1,Huo Yuqing1

Affiliation:

1. From Department of Medicine (W.Z., J.W., H.W., R.T., J.D.B., J.-G.G., A.S., C.Z., Y.H.), University of Minnesota, Minneapolis, Minn; INSERM U567 (B.V.), CNRS UMR8104, Department of Endocrinology, Metabolism and Cancer, Institut Cochin, Universite Paris 5, Paris, France; Department of Anesthesiology (C.Z.), New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ; Department of Nutrition and Food Science (C.W.), Texas A&M University, College Station, Tex;...

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 A 2A receptor antagonist) or AMP-activated protein kinase inhibitor compound C, and in macrophages lacking adenosine A 2A 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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