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A role of matrix metalloproteinase-8 in atherosclerosis.

ABSTRACT: Atherosclerotic lesions express matrix metalloproteinase (MMP)8, which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on nonmatrix proteins such as angiotensin (Ang) I.We studied whether MMP8 plays a role in atherogenesis.In atherosclerosis-prone apolipoprotein E-deficient mice, inactivating MMP8 resulted in a substantial reduction in atherosclerotic lesion formation. Immunohistochemical examinations showed that atherosclerotic lesions in MMP8-deficient mice had significantly fewer macrophages but increased collagen content. In line with results of in vitro assays showing that Ang I cleavage by MMP8 generated Ang II, MMP8 knockout mice had lower Ang II levels and lower blood pressure. In addition, we found that products of Ang I cleavage by MMP8 increased vascular cell adhesion molecule (VCAM)-1 expression and that MMP8-deficient mice had reduced VCAM-1 expression in atherosclerotic lesions. Intravital microscopy analysis showed that leukocyte rolling and adhesion on vascular endothelium was reduced in MMP8 knockout mice. Furthermore, we detected an association between MMP8 gene variation and extent of coronary atherosclerosis in patients with coronary artery disease. A relationship among MMP8 gene variation, plasma VCAM-1 level, and atherosclerosis progression was also observed in a population-based, prospective study.These results indicate that MMP8 is an important player in atherosclerosis.

SUBMITTER: Laxton RC

PROVIDER: S-EPMC2853782 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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A role of matrix metalloproteinase-8 in atherosclerosis.

Laxton Ross C RC Hu Yanhua Y Duchene Johan J Zhang Feng F Zhang Zhongyi Z Leung Kit-Yi KY Xiao Qingzhong Q Scotland Ramona S RS Hodgkinson Conrad P CP Smith Katherine K Willeit Johann J López-Otín Carlos C Simpson Iain A IA Kiechl Stefan S Ahluwalia Amrita A Xu Qingbo Q Ye Shu S

Circulation research 20090910 9

<h4>Rationale</h4>Atherosclerotic lesions express matrix metalloproteinase (MMP)8, which possesses proteolytic activity on matrix proteins particularly fibrillar collagens and on nonmatrix proteins such as angiotensin (Ang) I.<h4>Objective</h4>We studied whether MMP8 plays a role in atherogenesis.<h4>Methods and results</h4>In atherosclerosis-prone apolipoprotein E-deficient mice, inactivating MMP8 resulted in a substantial reduction in atherosclerotic lesion formation. Immunohistochemical exami ...[more]

PMID: 19745165

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Project description:ObjectivesMatrix metalloproteinase-8 messenger RNA expression was previously found to be increased in whole blood of children with septic shock. The impact of this finding on the severity and inflammatory response to sepsis is unknown. Here, we investigate the relationship between matrix metalloproteinase-8 and disease severity in children with septic shock. We further corroborate the role of matrix metalloproteinase-8 in sepsis in a murine model.DesignRetrospective observational clinical study and randomized controlled laboratory experiments.SettingPediatric intensive care units and an animal research facility at an academic children's hospital.Patients and subjectsPatients age ≤10 yrs admitted to the intensive care unit with a diagnosis of septic shock. For laboratory studies, we utilized male mice deficient for matrix metalloproteinase-8 and male wild-type C57BL/6J mice.InterventionsBlood from children with septic shock was analyzed for matrix metalloproteinase-8 messenger RNA expression and matrix metalloproteinase-8 activity, and correlated with disease severity based on mortality and degree of organ failure. A murine model of sepsis was used to explore the effect of genetic and pharmacologic inhibition of matrix metalloproteinase-8 on the inflammatory response to sepsis. Finally, activation of nuclear factor-κB was assessed both in vitro and in vivo.Measurements and main resultsIncreased matrix metalloproteinase-8 mRNA expression and activity in septic shock correlates with decreased survival and increased organ failure in pediatric patients. Genetic and pharmacologic inhibition of matrix metalloproteinase-8 leads to improved survival and a blunted inflammatory profile in a murine model of sepsis. We also identify matrix metalloproteinase-8 as a direct in vitro activator of the proinflammatory transcription factor, nuclear factor-κB.ConclusionsMatrix metalloproteinase-8 is a novel modulator of inflammation during sepsis and a potential therapeutic target.

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A role of matrix metalloproteinase-8 in atherosclerosis.

Publications

A role of matrix metalloproteinase-8 in atherosclerosis.

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