Abstract 250: Oxidative Stress Mediated Increase of HMGB-1 and RAGE cCntributes to Ascending Aortic Aneurysm Development in vivo.

Abstract

Background: Ascending-Thoracic Aortic Aneurysm (TAA) is a life-threatening condition for which the only treatment available is the surgical replacement/repair of the dilated aorta. It is known that oxidative stress (ROS) plays an important role in aortic wall remodeling involved in TAA: ROS induces pathological changes in vascular smooth muscle cells (VSMC) and triggers a disorganized and excessive production of matrix components and mediators of elastolysis. We demonstrated that chronic infusion of Angiotensin II (AngII) induces TAA formation in mice with concomitant accumulation of both ROS and synthetic VSMC, similar to that seen in human aneurysmal tissues. We also demonstrated that two ROS triggered molecules, the Receptor for Advanced Glycation end product (RAGE) and its ligand HMGB-1/amphoterin, are highly expressed in dysfunctional human aortic tissue. Recently a few microRNAs (miRs) have been proposed to play a role in aneurysm formation. We found that miR-143 is significantly down-regulated in human TAA tissues. We hypothesized that miR-143 may play a role in TAA development by regulating RAGE/HMGB-1 expression. Methods: RAGE and HMGB-1 expression was tested in control and aneurysmal human ascending aorta. C57BL6/J mice were fed a hypercholesterolemic diet and infused with saline or Ang II (1000 ng/kg/min) for 28 days. MiR-143, HMGB-1 and RAGE expression was evaluated by Western blotting and qPCR in murine ascending aorta samples and in human aortic VSMC treated with AngII (100nM) for 4 and 24 hrs. Results: Human aneurysmal aorta shows down-regulation of miR-143 concomitant with up-regulation HMGB-1 and RAGE expression. AngII infusion induces TAA in mice together with up-regulation of HMGB-1 and RAGE and miR-143 down-regulation. AngII treatment of VSMC induces RAGE and HMGB-1 expression and down-regulation of miR-143. A miR target analysis, using bioinformatic miR-mRNA algorithm tools, identified HMGB-1 as a direct target of miR-143. Conclusion: Our data suggest that miR-143, RAGE and HMGB-1 may cooperate in the process of aortic remodeling behind TAA formation. Further studies, investigating the interplay between miR-143 and HMGB-1/RAGE activation, may lead to potential new pharamacological targets for the treatment of TAA.