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


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 alpha1-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-kappaB pathways. In mice, acadesine suppressed lipopolysaccharide-mediated increases in blood coagulation, decreased TF expression in atherosclerotic lesions, and reduced deep vein thrombus formation.


CONCLUSIONS
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.
Zhang
Weiyu
W
Department of Medicine, University of Minnesota, 420 Delaware St SE, MMC508, Minneapolis, MN 55455, USA.
Wang
Jianguo
J
Wang
Huan
H
Tang
Rong
R
Belcher
John D
JD
Viollet
Benoit
B
Geng
Jian-Guo
JG
Zhang
Chunxiang
C
Wu
Chaodong
C
Slungaard
Arne
A
Zhu
Chuhong
C
Huo
Yuqing
Y
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D058917:Adenosine A2 Receptor Antagonists; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D001777:Blood Coagulation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000235:genetics; D012263:Ribonucleosides / Q000494:pharmacology*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation; D020246:Venous Thrombosis / Q000097:blood / Q000201:enzymology / Q000517:prevention & control*
D058917:Adenosine A2 Receptor Antagonists; D001057:Apolipoproteins E; D005343:Fibrinolytic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D012263:Ribonucleosides; D018808:Transcription Factor AP-1; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C440499:lipopolysaccharide, Escherichia coli O111 B4; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D013925:Thromboplastin; D019869:Phosphatidylinositol 3-Kinases; C548179:Prkaa1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases