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Nitric oxide elicits functional MMP-13 protein-tyrosine nitration during wound repair

Tania R. Lizarbe^*, Concepción García-Rama^*, Carlos Tarín^*, Marta Saura, Enrique Calvo^*, Juan Antonio López^*, Carlos López-Otín, Alicia R. Folgueras, Santiago Lamas and Carlos Zaragoza^*,1

^* Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;

Departamento de Fisiología, Facultad de Medicina, Universidad de Alcalá, Madrid, Spain;

Departamento de Bioquimica, Instituto Universitario de Oncologia, Universidad de Oviedo, Oviedo, Spain; and

Centro de Investigaciones Biológicas, Instituto "Reina Sofía" de Investigaciones Nefrológicas, Madrid, Spain

¹Correspondence: Fundación CNIC, Melchor Fernández Almagro 3, 28029 Madrid, Spain. E-mail: czaragoza{at}cnic.es

Nitric oxide (NO) plays a critical role in wound healing, in part by promoting angiogenesis. However, the precise repair pathways affected by NO are not well defined. We now show that NO regulates matrix metalloproteinase-13 (MMP-13) release during wound repair. We find that normally MMP-13 is kept inside endothelial cells by an association with caveolin-1. However, nitration of MMP-13 on tyrosine residue Y338 causes it to dissociate from caveolin-1 and be released from endothelial cells. We next explored the functional significance of MMP-13 nitration in vivo. Skin injury increases nitration of MMP-13 in mice. Skin wounds in inducible nitric oxide synthase knockout mice release less MMP-13 and heal more slowly than skin wounds in wild-type mice. Conversely, skin wounds in caveolin-1 knockout mice have increased NO production, increased MMP-13 nitration, and accelerated wound healing. Collectively, our data reveal a new pathway through which NO modulates wound repair: nitration of MMP-13 promotes its release from endothelial cells, where it accelerates angiogenesis and wound healing.—Lizarbe, T. R., García-Ram, C., Tarín, C., Saura, M., Calvo, E., López, J. A., López-Otín, C., Folgueras, A. R., Lamas, S., Zaragoza, C. Nitric oxide elicits functional MMP-13 protein-tyrosine nitration during wound repair.

Key Words: metalloproteinases • collagenase-3 • inducible nitric oxide synthase • caveolin-1 • wound healing

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