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

Lizarbe, Tania R.; García-Rama, Concepción; Tarin, Carlos; Saura, Marta; López, Juan Antonio; López-Otı́n, Carlos; Folgueras, Alicia R.; Lamas, Santiago; Zaragoza, Carlos

doi:10.1096/fj.07-103804

Cited by 39 publications

(40 citation statements)

References 34 publications

(32 reference statements)

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“…9,12 In addition, we also found that NO increases MMP-13 proteolytic activity by nitration of tyrosine residue 338. 13 Here we show that MMP-13 expression is not induced in atherosclerotic NOS3/apoE-null mice, suggesting that NOS3-mediated protection of atherosclerosis may at least be mediated by MMP-13.…”

Section: Discussionmentioning

confidence: 57%

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Endothelial Nitric Oxide Deficiency Reduces MMP-13–Mediated Cleavage of ICAM-1 in Vascular Endothelium

Tarin

Gómez

Calvo

et al. 2009

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Objective-Lack of endothelial nitric oxide synthase worsens atherosclerosis at least by increasing monocyte adhesion to endothelial cells. The purpose of this study was to elucidate the molecular mechanism elicited by NO. Methods and Results-We evaluated atherosclerosis in apoE and NOS3/apoE-deficient mice fed with high-cholesterol diet. We found significant increase in aortic lesion size, and infiltration of macrophages in NOS3/apoE-null mice when compared to apoE-deficient animals. To test the relevance of cellular adhesion as well as extracellular matrix degradation, we evaluated ICAM-1, VCAM-1, PECAM-1, MMP-2, MMP-9, MMP-12, MT1-MMP, and MMP-13 levels in mouse aortas. Lack of NO inhibits MMP-13 and increases ICAM-1 levels in atherosclerosis as compared to apoE-null mice. Ectopically expression of ICAM-1 in eukaryotic cells revealed that extracellular domain of ICAM-1 harbors a substrate recognized by MMP-13. Incubation of COS-7 cells expressing ectopic ICAM-1 in the presence of active MMP-13 induced inhibition of RAW 264.7 cell adhesion to COS-7 monolayers. MALDI-TOF MS analysis combined to Liquid chromatography coupled to Ion Trap MS on ICAM-1 incubated with MMP-13 allowed us to determine the cleavage sites of MMP-13 at positions E61 and G98 of ICAM-1. G98 is part of a PDGQS moiety, which shows homology with the consensus PDGLS substrate located at the MMP-13 cleaved site of type II collagen I-alpha. (ICAM-1). In aortas of apoE-null mice, ICAM-1 was found located in lesion-prone sites of the aorta, 2 and the importance of this inflammatory molecule was evidenced in atherosclerotic mice deficient in ICAM-1, which resulted protected from atherosclerotic lesions. 3 The role of matrix metalloproteinases (MMPs) has been analyzed in detail in late atherosclerosis. 4,5 However, the precise role of MMPs in the early steps of this pathology is still debated. In this regard, the effect of MMPs in the shedding of adhesion molecules was investigated in vitro, 6 although no data were reported in the context of atherosclerosis. Conclusions-TakingLack of endothelial NOS (eNOS, NOS3) increases leukocyte-endothelial adhesion, smooth muscle cell migration, platelet aggregation, and atherosclerosis in mice. 7,8 However, the mechanisms by which NOS3 could prevent atherosclerosis still remain unclear. Here we found that in atherosclerotic NOS3/apoE-deficient mice, increased monocyte adhesion, and a significant reduction of MMP-13 expression, were detected when compared to apoE-deficient animals. In addition, we found that MMP-13 cleaves ICAM-1 both in vivo and in vitro. Mass spectrometry analysis revealed 2 sites at positions E61 and G98, close to the ICAM-1 extracellular N-terminal domain. The relevance of MMP-13 and ICAM-1 on cellular adhesion was found in COS-7 cells expressing ectopic ICAM-1, in which RAW 264.7 cell adhesion was inhibited by the presence of active MMP-13. Our findings may help to explain at the molecular level the protective effect of endothelial NO in atherosclerosis. Methods ReagentsGeneral cell culture ...

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Section: Discussionmentioning

confidence: 57%

“…18 Interestingly, we found that peroxynitrite induces MMP-13 activation by nitration of tyrosine 338 of the protease. 13 Acute administration of BH4 or sepiapterin, a precursor of BH4, decreases superoxide production and improves endothelial function. 19 The role of matrix metalloproteinases in atherosclerosis has been proposed.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Nitric Oxide Deficiency Reduces MMP-13–Mediated Cleavage of ICAM-1 in Vascular Endothelium

Tarin

Gómez

Calvo

et al. 2009

ATVB

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“…MMPs play an important role in the proliferation and migration of several cell types, 18,21 but the impact of NOS3-mediated MMP regulation of neointimal hyperplasia is yet unknown. Here, we found that MMP-13 expression is increased in M1 and NO-treated M2 macrophages and induces migration of VSMC.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14][15] Macrophage inducible NOS (NOS2) drives the expression of several proinflammatory genes in M1 macrophages. 16 Nitric oxide induces the expression and activity of collagenase MMP-13, [17][18][19][20][21][22][23] which regulates proliferation and migration of several cell types. The effect of NO-mediated MMP expression on neointima formation is largely unknown.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

Nitric Oxide Prevents Aortic Neointimal Hyperplasia by Controlling Macrophage Polarization

Lavin

Gómez

Pello

et al. 2014

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Objective— Nitric oxide synthase 3 (NOS3) prevents neointima hyperplasia by still unknown mechanisms. To demonstrate the significance of endothelial nitric oxide in the polarization of infiltrated macrophages through the expression of matrix metalloproteinase (MMP)-13 in neointima formation. Approach and Results— After aortic endothelial denudation, NOS3 null mice show elevated neointima formation, detecting increased mobilization of LSK (lineage-negative [Lin]-stem-cell antigen 1 [SCA1]+KIT+) progenitor cells, and high ratios of M1 (proinflammatory) to M2 (resolving) macrophages, accompanied by high expression of interleukin-5, interleukin-6, MCP-1 (monocyte chemoattractant protein), VEGF (vascular endothelial growth factor), GM-CSF (granulocyte-macrophage colony stimulating factor), interleukin-1β, and interferon-γ. In conditional c-Myc knockout mice, in which M2 polarization is defective, denuded aortas showed extensive wall thickening as well. Conditioned medium from NOS3-deficient endothelium induced extensive repolarization of M2 macrophages to an M1 phenotype, and vascular smooth muscle cells proliferated and migrated faster in conditioned medium from M1 macrophages. Among the different proteins participating in cell migration, MMP-13 was preferentially expressed by M1 macrophages. M1-mediated vascular smooth muscle cell migration was inhibited when macrophages were isolated from MMP-13–deficient mice, whereas exogenous administration of MMP-13 to vascular smooth muscle cell fully restored migration. Excess vessel wall thickening in mice lacking NOS3 was partially reversed by simultaneous deletion of MMP-13, indicating that NOS3 prevents neointimal hyperplasia by preventing MMP-13 activity. An excess of M1-polarized macrophages that coexpress MMP-13 was also detected in human carotid samples from endarterectomized patients. Conclusions— These findings indicate that at least M1 macrophage-mediated expression of MMP-13 in NOS3 null mice induces neointima formation after vascular injury, suggesting that MMP-13 may represent a new promising target in vascular disease.

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“…MMPs also facilitate axonal regeneration in vitro (Zuo et al, 1998). During skin repair, nitration of MMP13 promotes its release from endothelial cells and accelerates healing (Lizarbe et al, 2008). Significantly, although MMP12 appears to inhibit corneal fibrosis, its activity has been associated with the development of lung pathology.…”

Section: Mmp12 Confers Protection Following Injurymentioning

confidence: 99%

Protective effects of matrix metalloproteinase-12 following corneal injury

Chan

Bertrand

et al. 2013

Journal of Cell Science

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SummaryCorneal scarring due to injury is a leading cause of blindness worldwide and results from dysregulated inflammation and angiogenesis during wound healing. Here we demonstrate that the extracellular matrix metalloproteinase MMP12 (macrophage metalloelastase) is an important regulator of these repair processes. Chemical injury resulted in higher expression of the fibrotic markers a-smooth muscle actin and type I collagen, and increased levels of angiogenesis in corneas of Mmp12 2/2 mice compared with corneas of wild-type mice. In vivo, we observed altered immune cell dynamics in Mmp12 2/2 corneas by confocal imaging. We determined that the altered dynamics were the result of an altered inflammatory response, with delayed neutrophil infiltration during the first day and excessive macrophage infiltration 6 days later, mediated by altered expression levels of chemokines CXCL1 and CCL2, respectively. Corneal repair returned to normal upon inhibition of these chemokines. Taken together, these data show that MMP12 has a protective effect on corneal fibrosis during wound repair through regulation of immune cell infiltration and angiogenesis.

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

Cited by 39 publications

References 34 publications

Endothelial Nitric Oxide Deficiency Reduces MMP-13–Mediated Cleavage of ICAM-1 in Vascular Endothelium

Endothelial Nitric Oxide Deficiency Reduces MMP-13–Mediated Cleavage of ICAM-1 in Vascular Endothelium

Nitric Oxide Prevents Aortic Neointimal Hyperplasia by Controlling Macrophage Polarization

Protective effects of matrix metalloproteinase-12 following corneal injury

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