Abstract 1560: Role of VAP-1, Eotaxin3, and MIG as Atherosclerotic Inflammatory Triggers of Severe Calcified and Stenotic Human Aortic Valves
Objectives: The pathophysiology of sclerotic aortic valve calcification is currently unknown. We demonstrated proinflammatory gene expression and its modulation by statin-therapy in severe calcified and stenotic human aortic valves (CSAV) using microarray technique. Our present study focuses on the specific gene-expression of vascular adhesion protein-1 (VAP-1), eotaxin3, and monokine-induced by γ-interferon (MIG) in CSAV. All three of them are known as triggers for atherosclerotic inflammation. Results were compared to their gene expression pattern in atherosclerotic lesions of carotid arteries.
Methods: CSAV were collected from patients undergoing aortic valve replacement with (CSAV+) and without preoperative statin-therapy (CSAV-). Transcriptional gene-profiling was evaluated by using real time PCR for confirmation. Results were compared with findings in normal aortic valves (C). Translational gene-profiling of inflammation was assessed (CSAV+, CSAV-, C) using specific immunohistochemical staining and results compared to atherosclerotic plaques of human carotid arteries.
Results: Direct comparison to C showed significant up regulation of eotaxin3, VAP-1, and MIG in CSAV-. Real-time PCR confirmed this significant upregulation using gene-specific primers: eotaxin3 (2.5±0.3 over C), VAP-1 (3.3±0.4), and MIG (2.9±0.5). Preoperative statin-therapy specifically altered gene expression of the investigated genes: whereas VAP-1 remained upregulated in CSAV+ (3.3±0.2 over C), eotaxin3 and MIG were significantly downregulated reaching the level of gene expression found in healthy aortic valves (eoxtaxin3 0.7±0.1 and MIG 1.6±0.5 over C). Immunohistochemical staining of protein expression in CSAV-, CSAV+, and C confirmed these significant results. Additionally, upregulated translational protein expression of VAP-1, eotaxin3, and MIG was also found in atherosclerotic plaques of carotid arteries.
Conclusions: Eotaxin3, MIG, and VAP-1 are potential inflammatory triggers of CSAVs. Statins down regulate eotaxin3 and MIG but not VAP-1 to a level found in healthy valves. Further studies are needed to evaluate potential inflammatory gene patterns and their therapeutic modulation in CSAV.