Nitric oxide elicits functional MMP-13 protein-tyrosine nitration during wound repair.
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
Tania R
TR
Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
García-Rama
Concepción
C
Tarín
Carlos
C
Saura
Marta
M
Calvo
Enrique
E
López
Juan Antonio
JA
López-Otín
Carlos
C
Folgueras
Alicia R
AR
Lamas
Santiago
S
Zaragoza
Carlos
C
D000595:Amino Acid Sequence; D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
D051242:Caveolin 1; D009569:Nitric Oxide; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D053509:Matrix Metalloproteinase 13