title: Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) results from persistent vasoconstriction, smooth muscle growth and extracellular matrix (ECM) remodelling of pulmonary arteries (PAs). Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in ECM turnover, and in smooth muscle cell (SMC) and endothelial cell migration and proliferation. MMP expression and activity are increased in experimental PAH. Therefore, this study investigated whether similar changes occur in idiopathic PAH (IPAH; formerly known as primary pulmonary hypertension). Both in situ and in vitro studies were performed on PAs from patients undergoing lung transplantation for IPAH and from patients treated by lobectomy for localised lung cancer, who served as controls. In IPAH, MMP-tissue inhibitor of metalloproteinase (TIMP) imbalance was found in cultured PA-SMCs, with increased TIMP-1 and decreased MMP-3. MMP-2 activity was markedly elevated as a result of increases in both total MMP-2 and proportion of active MMP-2. In situ zymography and immunolocalisation showed that MMP-2 was associated with SMCs and elastic fibres, and also confirmed the MMP-3-TIMP-1 imbalance. In conclusion, the findings of this study were consistent with a role for the matrix metalloproteinase-tissue inhibitor of metalloproteinase system in pulmonary vascular remodelling in idiopathic pulmonary arterial hypertension. The matrix metalloproteinase-tissue inhibitor of metalloproteinase imbalance may lead to matrix accumulation, and increased matrix metalloproteinase-2 activity may contribute to smooth muscle cell migration and proliferation. Whether these abnormalities are potential therapeutic targets deserves further investigation.
authors.affiliation: INSERM U492, Dépt de Physiologie, Faculté de Médecine, CHU Henri Mondor Créteil, 94010 Créteil, France. helene.lepetit@creteil.inserm.fr
authors.forename: H
authors.initials: H
authors.lastname: Lepetit
authors.forename: S
authors.initials: S
authors.lastname: Eddahibi
authors.forename: E
authors.initials: E
authors.lastname: Fadel
authors.forename: E
authors.initials: E
authors.lastname: Frisdal
authors.forename: C
authors.initials: C
authors.lastname: Munaut
authors.forename: A
authors.initials: A
authors.lastname: Noel
authors.forename: M
authors.initials: M
authors.lastname: Humbert
authors.forename: S
authors.initials: S
authors.lastname: Adnot
authors.forename: M-P
authors.initials: MP
authors.lastname: D'Ortho
authors.forename: C
authors.initials: C
authors.lastname: Lafuma
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D012016:Reference Values; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1