Abstract
AimsThis study investigated whether S100A4 plays a potential role in the formation of thoracic aortic aneurysm (TAA).Methods and ResultsThe thoracic aortas of male Sprague-Dawley rats were exposed to 0.5 M CaCl2 or normal saline (NaCl). Animals were euthanized at specified time-points (2, 4, and 10 weeks post-TAA induction). The treated aortic segments were harvested, and mRNA levels, protein expressions and immunohistochemistry of MMP-2, MMP-9 and S100A4 were analyzed. The A7r5 cell lines were used for an in vitro study. Experiments were also performed using human TAA samples for comparison. Localized aneurysmal dilation was observed in the CaCl2-treated segments. The transcription levels of S100A4 and MMPs were elevated in CaCl2-treated segments versus controls, and a significant correlation between S100A4 and expression of MMPs was observed across all time-points. Immunohistochemical studies revealed similar expression pattern of S100A4 and MMP 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). The proliferative ability of A7r5 cells after transfection with S100A4 siRNA was suppressed, and down-regulation of S100A4 inhibited MMP-2 and MMP-9 expression in vitro. Increased expression of S100A4 was observed in all layers of the aorta wall in human TAA specimens. Serum concentrations of S100A4 determined by ELISA were found to be significantly increased in TAA patients.ConclusionsThis study established the important roles of S100A4 and MMPs in the development of TAA.
Highlights
Aortic aneurysms are caused by extensive dilation of a weakened area of the aortic wall due to loss of normal structural integrity [1]
We report the coincidence of the spatiotemporal expression pattern between matrix metalloproteinase (MMP) and S100A4, a member of the S100 calcium-binding protein family largely known for its role in cancer cell metastasis [11], identified by our recent CaCl2-induced thoracic aortic aneurysm (TAA) animal study
These findings suggest that S100A4 contributes to TAA pathogenesis by functioning, at least partially, as a regulator of MMP expression
Summary
Aortic aneurysms are caused by extensive dilation of a weakened area of the aortic wall due to loss of normal structural integrity [1]. Since the dilated and over-stretched blood vessel walls are prone to rupture, often leading to sudden internal bleeding and death, aortic aneurysms represent a great risk to human life It is not entirely known why aortic aneurysms occur, accumulated studies have revealed that multiple environmental and genetic risk factors are involved in disease development, such as smoking, high blood pressure, high cholesterol, atherosclerosis, overweight and family history of aneurysms or other known genetic syndromes (e.g. Marfan syndrome, Ehlers-Danlos syndrome) [2]. Less conspicuously, disarrayed nodular proliferation of VSMCs in the subintima [3] or medial area [4] has been observed in association with specific genetic mutations The mechanisms underlying such pathological alterations have been extensively studied and many disease-associated genes have been identified: for example, the genes encoding VSMC intracellular contractile proteins [including Myosin heavy chain (MYH11) and a-smooth muscle actin (ACTA2)], the major TGF-beta receptor genes (TGFBR-1 and TGFBR-2), and the genes functioning as extracellular matrix elements such as Fibrillin-1 (FBN1) and Collagen a-1 (COL3A1) [2]. The pathogenic mechanisms leading to the activation of the MMP system in aneurysm development are still poorly defined
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