[en] OBJECTIVE: Significant alterations of the vascular wall occurs in abdominal aortic aneurysm (AAA) and atherosclerotic occlusive disease (AOD) that ultimately may lead to either vascular rupture or obstruction. These modifications have been ascribed to one or a group of proteases, their inhibitors or to the matrix macromolecules involved in the repair process without considering the extent of the observed variations. METHODS: The mRNA steady-state level of a large spectrum of proteolytic enzymes (matrix metalloproteinases: MMP-1, -2, -3, -8, -9, -11, -12, -13, -14; urokinase plasminogen activator: u-PA), their physiological inhibitors (tissue inhibitors of MMPs: TIMP-1, -2, -3; plasminogen activator inhibitor: PAI-1) and that of structural matrix proteins (collagens type I and III, decorin, elastin, fibrillins 1 and 2) was determined by RT-PCR made quantitative by using a synthetic RNA as internal standard in each reaction mixture. The profile of expression was evaluated in AAA (n=7) and AOD (n=5) and compared to non-diseased abdominal (CAA, n=7) and thoracic aorta (CTA, n=5). RESULTS: The MMPs -8, -9, -12 and -13 mostly associated with inflammatory cells were not or barely detected in CAA and CTA while they were largely and similarly expressed in AAA and AOD. Expression of protease inhibitors or structural proteins were only slightly increased in both pathological conditions with the exception of elastin which was reduced. The main significant difference between AAA and AOD was a lower expression of TIMP-2 and PAI-1 in the aneurysmal lesions. CONCLUSIONS: The remodeling of the aortic wall in AAA and AOD involves gene activation of a large and similar spectrum of proteolytic enzymes while the expression of two physiological inhibitors, TIMP-2 and PAI-1, is significantly lower in AAA compared to AOD. The repair process in the aneurysmal disease seems similar to that of the occlusive disease.
Disciplines :
Biochemistry, biophysics & molecular biology Surgery
Author, co-author :
Defawe, Olivier D; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Colige, Alain ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Lambert, Charles ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Munaut, Carine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Lapiere, Charles M
Limet, Raymond ; Université de Liège - ULiège > Département des sciences cliniques > Chirurgie Cardio-vasculaire et thoracique - CHU
Nusgens, Betty ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
SakalihasanN, Natzi ; Centre Hospitalier Universitaire de Liège - CHU > Chirurgie cardio-vasculaire
Language :
English
Title :
TIMP-2 and PAI-1 mRNA levels are lower in aneurysmal as compared to athero-occlusive abdominal aortas.
Ghorpade A., Baxter B.T. Biochemistry and molecular regulation of matrix macromolecules in abdominal aortic aneurysms. Ann NY Acad Sci. 800:1996;138-150.
Sakalihasan N., Heyeres A., Nusgens B.V., et al. Modifications of the extracellular matrix of aneurysmal abdominal aortas as a function of their size. Eur J Vasc Surg. 7:1993;633-637.
Koch A.E., Haines G.K., Rizzo R.J., et al. Human abdominal aortic aneurysms: Immunophenotypic analysis suggesting an immune-mediated response. Am J Pathol. 137:1990;1199-1213.
Sternlicht M.D., Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 17:2001;463-516.
Knox J.B., Sukhova G.K., Whittemore A.D., et al. Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Circulation. 95:1997;205-212.
Mesh Ch L., Baxter B.T., Pearce W.H., et al. Collagen and elastin gene expression in aortic aneurysms. Surgery. 112:1992;256-262.
Baxter B.T., McGee G.S., Shively V.P., et al. Elastin content, cross-links, and mRNA in normal and aneurysmal human aorta. J Vasc Surg. 16:1992;192-200.
Huffman M.D., Curci J.A., Moore G., et al. Functional importance of connective tissue repair during the development of experimental abdominal aortic aneurysms. Surgery. 128:2000;429-438.
Chirgwin J.M., Przybyla A.E., MacDonald R.J., et al. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 18:1979;5294-5299.
Lambert Ch.A., Colige A.C., Munaut C., et al. Distinct pathways in the overexpression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension. Matrix Biol. 20:2001;397-408.
Lambert Ch.A., Colige A.C., Lapière Ch.M., et al. Coordinated regulation of procollagens I and III and their post-translational enzymes by dissipation of mechanical tension in human dermal fibroblasts. Eur J Cell Biol. 80:2001;479-485.
Nusgens B., Humbert P., Rougier A., et al. Topically applied vitamin C enhances the mRNA level of collagens I and III, their processing enzymes and TIMP1 in the human dermis. J Invest Dermatol. 116:2001;853-859.
Sakalihasan N., Delvenne Ph., Nusgens B.V., et al. Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms. J Vasc Surg. 24:1996;127-133.
Carrell T.W.G., Burnand K.G., Wells G.M.A., et al. Stromelysin-1 (matrix metalloproteinase-3) and tissue inhibitor of metalloproteinase-3 are overexpressed in the wall of abdominal aortic aneurysms. Circulation. 105:2002;477-482.
Godfrey M., Nejezchleb P.A., Schaefer G.B., et al. Elastin and fibrillin mRNA and protein levels in the ontogeny of normal human aorta. Connect Tissue Res. 29:1993;61-69.
Pyo R., Lee J.K., Shipley J.M., et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest. 105:2000;1641-1649.
Armstrong P.J., Johanning J.M., Calton W.C., et al. Differential gene expression in human abdominal aorta: aneurysmal versus occlusive disease. J Vasc Surg. 35:2002;346-355.
McMillan W.D., Patterson B.K., Keen R.R., et al. In situ localization and quantification of mRNA for 92-kD type IV collagenase and its inhibitor in aneurysmal, occlusive, and normal aorta. Arterioscler Thromb Vasc Biol. 15:1995;1139-1144.
Patel M.I., Melrose J., Ghosh P., et al. Increased synthesis of matrix metalloproteinases by aortic smooth muscle cells is implicated in the etiopathogenesis of abdominal aortic aneurysms. J Vasc Surg. 24:1996;82-92.
Mao D.L., Lee J.K., Vanvickle S.J., et al. Expression of collagenase-3 (MMP-13) in human abdominal aortic aneurysms and vascular smooth muscle cells in culture. Biochem Biophys Res Commun. 261:1999;904-910.
Knauper V., Smith B., Lopez-Otin C., et al. Activation of progelatinase B (proMMP-9) by active collagenase-3 (MMP-13). Eur J Biochem. 248:1997;369-373.
Herman M.P., Sukhova G.K., Libby P., et al. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma - A novel collagenolytic pathway suggested by transcriptional profiling. Circulation. 104:2001;1899-1904.
Carmeliet P., Moons L., Lijnen R., et al. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet. 17:1997;439-444.
Allaire E., Hasenstab D., Kenagy R.D., et al. Prevention of aneurysm development and rupture by local overexpression of plasminogen activator inhibitor-1. Circulation. 98:1998;249-255.
Wang X., Tromp G., Cole W., et al. Analysis of coding sequences for tissue inhibitor of metalloproteinases 1 (TIMP1) and 2 (TIMP2) in patients with aneurysms. Matrix Biol. 18:1999;121-124.
Strongin A.Y., Collier I., Bannikov G., et al. Mechanism of cell surface activation of 72-kDa type IV collagenase. J Biol Chem. 270:1995;5331-5338.
Noel A., Boulay A., Kebers F., et al. Demonstration in vivo that stromelysin-3 functions through its proteolytic activity. Oncogene. 19:2000;1605-1612.
Ikari Y., Mulvihill E., Schwartz S.M. Alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and alpha 2-macroglobulin are the antiapoptotic factors of vascular smooth muscle cells. J Biol Chem. 276:2001;11798-11803.
Mitchell M.B., McAnena O.J., Rutherford R.B. Ruptured mesenteric artery aneurysm in a patient with alpha 1-antitrypsin deficiency: etiologic implications. J Vasc Surg. 17:1993;420-424.
Yamashita A., Noma T., Nakazawa A., et al. Enhanced expression of matrix metalloproteinase-9 in abdominal aortic aneurysms. World J Surg. 25:2001;259-265.
Thompson R.W., Holmes D.R., Mertens R.A., et al. Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. J Clin Invest. 96:1995;318-326.
Lysiak J.J., Hussaini I.M., Gonias S.L. α2-Macroglobulin synthesis by the human monocytic cell line THP-1 is differentiation state-dependent. J Cell Biochem. 67:1997;492-497.
Ye S., Eriksson P., Hamsten A., et al. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 271:1996;13055-13060.
Zhang B.P., Ye S., Herrmann S.M., et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 99:1999;1788-1794.
Sakalihasan N., Van Damme H., Gomez P., et al. Positron emission tomography (PET) evaluation of abdominal aortic aneurysm. Eur J Vasc Endovasc Surg. 23:2002;431-436.