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Vascular Biology

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

Goran Marinković, Stijntje Hibender, Mark Hoogenboezem, Amber van Broekhoven, Arginell F. Girigorie, Natascha Bleeker, Anouk A.J. Hamers, Jan Stap, Jaap D. van Buul, Carlie J.M. de Vries, Vivian de Waard
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https://doi.org/10.1161/ATVBAHA.113.301394
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301394
Originally published August 15, 2013
Goran Marinković
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Stijntje Hibender
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Mark Hoogenboezem
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Amber van Broekhoven
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Arginell F. Girigorie
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Natascha Bleeker
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Anouk A.J. Hamers
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Jan Stap
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Jaap D. van Buul
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Carlie J.M. de Vries
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Vivian de Waard
From the Department of Medical Biochemistry (G.M., S.H., A.v.B., A.F.G., N.B., A.A.J.H., C.J.M.d.V., V.d.W.), Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory (M.H., J.D.v.B.), and Department of Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, The Netherlands.
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Abstract

Objective—In aortic aneurysms the arterial vessel wall is dilated because of destruction of its integrity, which may lead to lethal vessel rupture. Chronic infiltration of inflammatory cells into the vessel wall is fundamental to aneurysm pathology. We aim to limit aneurysm growth by inhibition of inflammation and reducing endothelial cell (EC) activation with immunosuppressive drug azathioprine (Aza).

Approach and Results—Aza and its metabolite 6-mercaptopurine have anti-inflammatory effects on leukocytes. We here demonstrate that treatment of ECs with 6-mercaptopurine inhibits cell activation as illustrated by reduced expression of interleukin-12, CCL5, CCL2, and vascular cell adhesion molecule-1 and inhibition of monocyte–EC adhesion. The underlying mechanism of 6-mercaptopurine involves suppression of GTPase Rac1 activation, resulting in reduced phosphorylation of c-Jun-terminal-N-kinase and c-Jun. Subsequently, the effect of Aza was investigated in aneurysm formation in the angiotensin II aneurysm mouse model in apolipoprotein E–deficient mice. We demonstrated that Aza decreases de novo aortic aneurysm formation from an average aneurysm severity score of 2.1 (control group) to 0.6 (Aza group), and that Aza effectively delays aorta pathology in a progression experiment, resulting in a reduced severity score from 2.8 to 1.7 in Aza-treated mice. In line with the in vitro observations, Aza-treated mice showed less c-Jun-terminal-N-kinase activation in ECs and reduced leukocyte influx in the aortic wall.

Conclusions—The immunosuppressive drug Aza has an anti-inflammatory effect and in ECs inhibits Rac1 and c-Jun-terminal-N-kinase activation, which may explain the protective effect of Aza in aneurysm development and, most importantly for clinical implications, aneurysm severity.

  • aneurysm
  • endothelium
  • inflammation
  • Received February 18, 2013.
  • Accepted July 29, 2013.
  • © 2013 American Heart Association, Inc.
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    Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells
    Goran Marinković, Stijntje Hibender, Mark Hoogenboezem, Amber van Broekhoven, Arginell F. Girigorie, Natascha Bleeker, Anouk A.J. Hamers, Jan Stap, Jaap D. van Buul, Carlie J.M. de Vries and Vivian de Waard
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301394, originally published August 15, 2013
    https://doi.org/10.1161/ATVBAHA.113.301394

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    Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells
    Goran Marinković, Stijntje Hibender, Mark Hoogenboezem, Amber van Broekhoven, Arginell F. Girigorie, Natascha Bleeker, Anouk A.J. Hamers, Jan Stap, Jaap D. van Buul, Carlie J.M. de Vries and Vivian de Waard
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;ATVBAHA.113.301394, originally published August 15, 2013
    https://doi.org/10.1161/ATVBAHA.113.301394
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