Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN.
Nitric Oxide (NO) is involved in the development and progression of abdominal aortic aneurysms (AAA). We found that inhibition of inducible NO synthase (iNOS) protects mice in an elastase-induced AAA model, significantly inhibiting the production of matrix metalloproteinase-13 (MMP-13). The extracellular MMP inducer (EMMPRIN; CD147) was increased in human AAA biopsies and in wild-type murine AAA but not in AAA from iNOS null mice. In cells overexpressing ectopic EMMPRIN, MMP-13 secretion was stimulated, whereas silencing of EMMPRIN by RNA interference led to significant inhibition of MMP-13 expression. In addition, elastase infusion of MMP-13 null mouse aortas induced a significant increase of EMMPRIN but reduced aortic dilatation when compared with wild-type mice, suggesting that NO-mediated AAA may be mediated through EMMPRIN induction of MMP-13. These findings were further verified in elastase-infused iNOS null mice, in which daily administration of NO caused a significant aortic dilatation and the expression of EMMPRIN and MMP-13. By contrast, in iNOS wild-type mice, pharmacological inhibition of iNOS by administration of 1400 W induced a reduction of aortic diameter and inhibition of MMP-13 and EMMPRIN expression when compared with control mice. Our results suggest that NO may regulate the development of AAA in part by inducing the expression of EMMPRIN and modulating the activity of MMP-13 in murine and human aneurysms.
Institutional Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain.
Tania R
TR
Lizarbe
Carlos
C
Tarín
Mónica
M
Gómez
Begoña
B
Lavin
Enrique
E
Aracil
Luis M
LM
Orte
Carlos
C
Zaragoza
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology* / Q000473:pathology*; D051926:Basigin / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000201:enzymology / Q000473:pathology; D004790:Enzyme Induction; D005110:Extracellular Space / Q000201:enzymology; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D051926:Basigin; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D053509:Matrix Metalloproteinase 13