mercaptopurine and Aortic-Aneurysm

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).. 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.. 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.

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents; Aortic Aneurysm; Aortic Rupture; Apolipoproteins E; Azathioprine; Cell Line, Tumor; Coculture Techniques; Disease Models, Animal; Disease Progression; Endothelial Cells; Enzyme Activation; Human Umbilical Vein Endothelial Cells; Humans; Immunosuppressive Agents; Inflammation Mediators; JNK Mitogen-Activated Protein Kinases; Mercaptopurine; Mice; Mice, Knockout; Monocytes; Neuropeptides; Phosphorylation; Protein Kinase Inhibitors; rac1 GTP-Binding Protein; Signal Transduction

Topics: Adult; Aorta, Thoracic; Aortic Aneurysm; Aortic Valve Insufficiency; Biopsy; Cartilage Diseases; Digitalis Glycosides; Hearing Disorders; Heart Valves; Humans; Male; Marfan Syndrome; Mercaptopurine; Nose Deformities, Acquired; Papain; Polychondritis, Relapsing; Prednisone; Vertigo