Abstract 97: Spatiotemporal Expression Of Matrix Metalloproteinases (mmps) Is Regulated By Ca2+-signal Transducer S100a4 In The Thoracic Aortic Aneurysm Pathogenesis

Abstract

Purpose: Ca 2+ signaling pathways play critical roles in a wide range of physiological functions including control and regulation of smooth muscle cell performance and vascular tone. Previous studies have indicated that Ca 2+ signaling transducer S100A4 could increase the secretion of MMPs from endothelial cells and fibroblasts and is greatly expressed in smooth muscle cells in atherosclerotic lesions. This study investigated whether S100A4 has a potential role in the formation of TAA. Methods: Thoracic aorta of male Sprague-Dawley rats was exposed to 0.5 M CaCl 2 or normal saline (NaCl). Animals were euthanized at specified time points (2, 4, 10 weeks post-TAA induction). The treated aortic segments were harvested, and mRNA levels, protein expressions and immunohistochemistry regarding MMP-2, MMP-9 and S100A4 were analyzed. The A7r5 cell lines were used as in vitro study. Experiments were also performed using human TAA samples for comparison. Results: Localized aneurysmal dilation was observed in the CaCl 2 -treated segments, with disruption of elastic lamellae and decrease of intima-media thickness (minimum at 2 weeks). The transcription levels of S100A4 and MMPs were elevated in CaCl 2 -treated segments versus controls (most prominent at 2 weeks), and a significant correlation between S100A4 and MMPs expression was observed across the time points (MMP-2, r=0.652, p<0.05; MMP-9, r=0.762, p<0.05). Immunohistochemistry studies have revealed similar expression pattern of S100A4 and MMPs proteins, as well as co-localization of S100A4 with the cell lineage markers (αSMA and CD68) and inflammatory markers (MMPs and NF-κB P65 subunit). Proliferation ability of A7r5 cells after transfection with S100A4 siRNA was suppressed and down regulation of S100A4 inhibited MMP-2 expression in vitro . Increased expression of S100A4 was observed in the entire layers of aorta wall in human TAA specimens. And serum concentrations of S100A4 determined by ELISA were found significantly increased in TAA patients. Conclusion: This study established an important role of S100A4 with MMPs in the development of TAA. S100A4 may serve as a biomarker for TAA diagnosis and a potential target for therapy.