Matrix metalloproteinase 2 is suppressed by trapidil, a CD40-CD40 ligand pathway inhibitor, in human abdominal aortic aneurysm wall.
BACKGROUND
The activation of inflammatory cells and the production of matrix metalloproteinases (MMPs) are important in the pathogenesis of abdominal aortic aneurysm (AAA). Previous studies have demonstrated that the antiplatelet agent trapidil has multiple actions, including suppression of MMP expression through the inhibition of the CD40-CD40 ligand (CD40-CD40L) pathway in cultured cells. A recent clinical study suggested that trapidil might have functions beyond its antiplatelet action. Methods and results In the present study, we performed immunohistochemical analysis and semiquantitative reverse transcription-polymerase chain reaction to evaluate the effect of trapidil on the production of MMPs in cultured aortic tissues from patients with infrarenal AAA (n = 9) and control patients with aortoiliac occlusive disease (n = 7). The tissue concentrations of both MMP-2 and MMP-9 were significantly higher in AAA walls than in control aortic walls. Both trapidil and an anti-CD154 (CD40L) antibody significantly suppressed the protein production and mRNA expression of MMP-2 but did not inhibit those of MMP-9 in organ cultures of AAA wall specimens. MMP-9 was produced by macrophages and a lot of neutrophils in AAA tissues, whereas MMP-2 was derived from macrophages. CD40 was expressed on macrophages but not on neutrophils, and this expression could explain the differential effect of trapidil on the production of MMP-2 and MMP-9.


CONCLUSIONS
Trapidil, a CD40-CD40L pathway inhibitor, suppressed mRNA expression and protein production of MMP-2 in AAA tissues, suggesting a potential therapeutic approach for the prevention or treatment of AAA.
Nagashima
Hirotaka
H
Department of Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Tokyo, Japan. mnagasih@hij.twmu.ac.jp
Aoka
Yoshikazu
Y
Sakomura
Yasunari
Y
Uto
Kenta
K
Sakuta
Akiko
A
Aomi
Shigeyuki
S
Kurosawa
Hiromi
H
Hagiwara
Nobuhisa
N
Kawana
Masatoshi
M
Kasanuki
Hiroshi
H
D017544:Aortic Aneurysm, Abdominal / Q000473:pathology*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D016022:Case-Control Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014192:Trapidil / Q000494:pharmacology*
D019013:CD40 Antigens; D061965:Matrix Metalloproteinase Inhibitors; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D023201:CD40 Ligand; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D014192:Trapidil