Abstract 5883: Acadesine Inhibits Tissue Factor Induction and Thrombus Formation by Activating the Phosphoinositide 3-Kinase/Akt Signaling Pathway
Background-Acadesine, an adenosine-regulating agent (ARA) and activator for AMP-activated protein kinase (AMPK), protects patients with coronary artery bypass graft (CABG) surgery from myocardial ischemia-reperfusion injury. The precise mechanism for this effect remains to be defined. Tissue factor (TF) has been recognized to play an important role in myocardial ischemia-reperfusion injury. This study aims to investigate whether and how acadesine inhibits TF expression and thrombus formation.
Methods and Results-Human umbilical vein endo-thelial cells (HUVECs) and human peripheral blood monocytes were stimulated with LPS and followed with acadesine treatment. Acadesine dramatically suppressed the clotting activity of TF, TF expression at protein and mRNA levels. These inhibitory effects of acadesine remain unchanged for endothelial cells treated with ZM 241385, a specific adenosine A2A receptor (A2AR) antagonist, or AMPK inhibitor compound C, and macrophages lacking A2AR or α1-AMPK. In both endothelial cells and macrophages, acadesine activated the phosphoinositide 3-kinase(PI3K)/Akt signaling pathway, reduced activity of mitogen-activated protein kinases (MAPKs), and consequently suppressed TF expression by inhibition of activator protein-1 (AP-1) and nuclear factor κB (NF- κB) pathways. In mice acadesine suppressed LPS-mediated increased blood coagulation, decreased TF expression in atherosclerotic lesions, and reduced thrombus formation in a deep vein thrombosis model.
Conclusions-Acadesine inhibits TF expression and thrombus formation by activating PI3K-Akt pathway. This may be one of major mechanisms for its beneficial effect for reducing acute post-reperfusion myocardial infarction (MI) and improvement of long-term survival in patients who develop a perioperative MI. This novel finding implicates that acadesine is potentially useful in the treatment of many cardiac or non-cardiac events associated with thrombotic pathology such as angina pain, deep vein thrombosis and sepsis.