Spatiotemporal expression of matrix metalloproteinases (MMPs) is regulated by the Ca2+-signal transducer S100A4 in the pathogenesis of thoracic aortic aneurysm.
OBJECTIVE
This study investigated whether S100A4 plays a potential role in the formation of thoracic aortic aneurysm (TAA).


RESULTS
The 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.


CONCLUSIONS
This study established the important roles of S100A4 and MMPs in the development of TAA.
Department of Geratology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Jiumei
J
Cao
Liang
L
Geng
Qihong
Q
Wu
Wei
W
Wang
Qiujing
Q
Chen
Lin
L
Lu
Weifeng
W
Shen
Ying
Y
Chen
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D051996:Transcription Factor RelA; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C499412:S100a4 protein, rat