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Low tissue inhibitor of metalloproteinases 3 and high matrix metalloproteinase 14 levels defines a subpopulation of highly invasive foam-cell macrophages.

ABSTRACT: OBJECTIVE:An excess of metalloproteinases (MMPs) over tissue inhibitors of metalloproteinases (TIMPs) may favor atherosclerotic plaque rupture. We compared TIMP levels in nonfoamy and foam-cell macrophages (FCM) generated in vivo. METHODS AND RESULTS:In vivo generated rabbit FCM exhibited 84% reduced TIMP-3 protein compared to nonfoamy macrophages, and immunocytochemistry revealed a TIMP-3 negative subset (28%). Strikingly, only TIMP-3 negative FCM invaded a synthetic basement membrane, and invasion was inhibited by exogenous TIMP-3. TIMP-3 negative FCM also had increased proliferation and apoptosis rates compared to TIMP-3 positive cells, which were retarded by exogenous TIMP-3; this also reduced gelatinolytic activity. TIMP-3 negative FCM were found at the base of advanced rabbit plaques and in the rupture-prone shoulders of human plaques. To explain the actions of low TIMP-3 we observed a 26-fold increase in MT1-MMP (MMP-14) protein in FCM. Adding an MT1-MMP neutralizing antibody reduced foam-cell invasion, apoptosis, and gelatinolytic activity. Furthermore, MT1-MMP overexpressing and TIMP-3 negative FCM were found at the same locations in atherosclerotic plaques. CONCLUSIONS:These results demonstrate that TIMP-3 is downregulated in a distinct subpopulation of FCM which have increased MMP-14. These cells are highly invasive and have increased proliferation and apoptosis, all properties expected to destabilise atherosclerotic plaques.

SUBMITTER: Johnson JL

PROVIDER: S-EPMC2851011 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Low tissue inhibitor of metalloproteinases 3 and high matrix metalloproteinase 14 levels defines a subpopulation of highly invasive foam-cell macrophages.

Johnson Jason L JL Sala-Newby Graciela B GB Ismail Yasmin Y Aguilera Concepción M CM Newby Andrew C AC

Arteriosclerosis, thrombosis, and vascular biology 20080619 9

<h4>Objective</h4>An excess of metalloproteinases (MMPs) over tissue inhibitors of metalloproteinases (TIMPs) may favor atherosclerotic plaque rupture. We compared TIMP levels in nonfoamy and foam-cell macrophages (FCM) generated in vivo.<h4>Methods and results</h4>In vivo generated rabbit FCM exhibited 84% reduced TIMP-3 protein compared to nonfoamy macrophages, and immunocytochemistry revealed a TIMP-3 negative subset (28%). Strikingly, only TIMP-3 negative FCM invaded a synthetic basement mem ...[more]

PMID: 18566294

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Project description:This study aimed to determine whether a novel nutrient mixture (NM), composed of lysine, ascorbic acid, proline, green tea extracts and other micronutrients, attenuates impairments induced by spinal cord injury (SCI) and to investigate the related molecular mechanisms. A mouse model of SCI was established. Thirty-two mice were divided into four groups. The sham group received vehicle only. The SCI groups were treated orally with saline (saline group), a low dose (500 μg 3 times/day) of NM (NM-LD group) or a high dose (2,000 μg 3 times/day) of NM (NM-HD group). The levels of mouse hindlimb movement were determined every day in the first week post-surgery. The protein expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were determined by western blotting. Wild-type and mutant MMP-2- and MMP-9-directed luciferase constructs were generated and their luciferase activities were determined. NM significantly facilitated the recovery of hindlimb movement of the mice in comparison to that in the saline group. The expression levels of MMP-2 in the NM-LD and NM-HD groups were decreased by ~50% compared with the saline group as indicated by western blotting results. The expression levels of MMP-9 in the NM-LD and NM-HD groups were decreased to ~25 and ~10%, respectively. These results suggest that NM significantly inhibits the expression of MMP-2 and MMP-9 proteins. Reverse transcription quantitative polymerase chain reaction results indicated that NM reduced the levels of MMP-2 and MMP-9 mRNA. Furthermore, the luciferase results indicated that site-directed mutagenesis comprising a -1306 C to T (C/T) base change in the MMP-2 promoter and a -1562 C/T base change in the MMP-9 promoter abolished the inhibitory effects of NM on MMP-2 and MMP-9 promoters. These results suggest that NM attenuates SCI-induced impairments in mice movement by negatively affecting the promoter activity of MMP-2 and MMP-9 genes and thus decreasing the expression of MMP-2 and MMP-9 proteins.

Dataset Information

Low tissue inhibitor of metalloproteinases 3 and high matrix metalloproteinase 14 levels defines a subpopulation of highly invasive foam-cell macrophages.

Publications

Low tissue inhibitor of metalloproteinases 3 and high matrix metalloproteinase 14 levels defines a subpopulation of highly invasive foam-cell macrophages.

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