Par-1 activation by metalloproteinase-1 (mmp-1)

Details Par-1 activation by metalloproteinase-1 (mmp-1) Par-1 activation by metalloproteinase-1 (mmp-1)

C - Chemistry, Metallurgy

07

K

C07K 14/705 (2006.01) C12N 5/07 (2010.01) A61K 31/443 (2006.01) A61K 31/65 (2006.01) A61K 38/16 (2006.01) A61P 9/10 (2006.01) C12Q 1/02 (2006.01) C12Q 1/37 (2006.01) C12Q 1/68 (2006.01) G01N 33/50 (2006.01) G01N 33/68 (2006.01) A61L 31/16 (2006.01) C12N 9/50 (2006.01)

Patent

CA 2758322

Matrix metalloproteases (MMPs) play many important roles in normal and pathological remodeling processes including atherothrombotic disease, inflammation, angiogenesis and cancer. This invention relates to the activation of protease-activated receptor-1 (PAR-1) by endogenous platelet MMP-1 collagenase on the surface of platelets. Exposure of platelets to fibrillar collagen converts the surface-bound pro-MMP-1 zymogen to active MMP- 1, which promotes aggregation through PAR-1, MMP-1 is shown to cleave the PAR-1 extracellular domain at a novel site, which then strongly activates Rho-GTP signaling pathways, cell shape change and motility, and MAPK signaling. Blockade of MMP-PAR 1 suppresses thrombogenesis under arterial flow conditions and inhibited thrombosis in animals. These studies provide a link between matrix-dependent activation of metalloproteases and platelet-G protein signaling and identify MMP- 1/PAR-1 as a new target for the treatment and prevention of arterial thrombosis and other thrombotic diseases.

Les métalloprotéases matricielles (MMP : matrix metalloproteases) jouent plusieurs rôles importants dans des procédés de remodelage normaux et pathologiques comprenant une maladie athérothrombotique, une inflammation, l'angiogenèse et le cancer. L'invention concerne également l'activation du récepteur-1 activé par la protéase (PAR-1) par la collagénase plaquettaire endogène MMP-1 à la surface des plaquettes. L'exposition des plaquettes au collagène fibrillaire convertit la proenzyme pro-MMP-1 liée à la surface en MMP-1 active, ce qui favorise l'agrégation par le PAR-1. La MMP-1 s'est avéré couper le domaine extracellulaire du PAR-1 en un nouveau site, ce qui active fortement les voies de signalisation de la Rho-GTP, le changement de la forme des cellules et la motilité, et la signalisation par la MAPK. Le blocage des MMP-PAR-1 supprime la thrombogenèse dans des conditions de flux artériel et inhibe la thrombose chez les animaux. Ces études fournissent un lien entre l'activation dépendant de la matrice des métalloprotéases et la signalisation des protéines G couplées aux plaquettes et identifient le MMP-1/PAR-1 comme nouvelle cible pour le traitement ou la prévention de la thrombose artérielle et d'autres maladies thrombotiques.

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