Abstract 18727: RAGE-HMGB-1 Expression in the Ascending Aorta of Bicuspid Aortic Valve (BAV) Patients Correlates With Circulating SRAGE and May Predict Vascular Dysfunction Associated With BAV Disease

Abstract

Introduction: Bicuspid Aortic Valve (BAV) is associated with premature valve and vascular complications. Thirty to 50% of BAV patients require surgery for valve diseases and/or ascending aorta (AA) dilatation. Increasing studies suggest that the measure of AA diameter, as criteria for aortic surgery, is an imperfect predictor of dissection and rupture. Therefore there is a need to identify reliable markers of dysfunctional AA to guide the decision for surgery. Recently, Advanced glycation end products (AGEs), such as HMGB-1 and S100A12, and their binding to the Receptor for AGE (RAGE) have been associated to mechanisms of valve and vascular degeneration. We previously demonstrated that BAV patients have higher plasma levels of the soluble form of RAGE (sRAGE) when compared with tricuspid aortic valve (TAV) patients. We also showed that the AA of BAV patients with higher circulating sRAGE is characterized by severe elastin degradation and matrix disorganization when compared to those with lower sRAGE. Hypothesis: We hypothesized that the level of circulating sRAGE may be related to the expression of AGEs and RAGE in the AA. Methods: HMGB-1 and S100A12 plasma values were measured by ELISA in BAV (N=20) and TAV (N=20) patients previously tested for sRAGE. Logistic regression and multivariate analysis were performed. AA tissue from BAV patients with sRAGE concentration ranging from 491 pg/mL to 5978 pg/mL were tested for the expression of RAGE, HMGB-1 and S100A12 by immunohistochemistry and Western blotting. Results: RAGE expression linearly increased in the AA of BAV patients with higher plasma sRAGE (R2=0.5). RAGE and sRAGE levels correlate with the expression of HMGB-1. S100A12 was minimally detected and restricted to inflammatory infiltrates in both BAV and TAV patients with AA dilatation. Plasma level of S100A12 and HMGB-1 were not significantly different in BAV patients when compared to TAV and did not correlate with sRAGE concentration. Conclusions: These results suggest that HMGB1-mediated RAGE activation in the AA of BAV patients may be responsible for tissue degeneration and increased sRAGE release in the bloodstream. The interaction AGE-RAGE in the AA of BAV patients may help in evaluating the risk for rapid AA degeneration independently of dilation.