title: Differential effects of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 on atherosclerosis and monocyte/macrophage invasion.
abstract: OBJECTIVE
  MMPs contribute to atherosclerotic plaque progression and instability, but the relative potency of their endogenous tissue inhibitors of metalloproteinases (TIMPs) as protective factors has not been defined. We therefore investigated the impact of TIMP-1 and TIMP-2 knockout on atherosclerotic plaque burden and composition in apolipoprotein E-knockout (Apoe(-/-)) mice and studied the underlying effects on monocyte/macrophage behaviour.
  
  
  RESULTS
  Analysis of brachiocephalic artery plaques revealed comparable atherosclerotic lesion areas between TIMP-1(-/-) Apoe(-/-) or TIMP-2(-/-) Apoe(-/-) double deficient mice and relevant age-matched, strain-matched Apoe(-/-) controls after 8 weeks of high-fat feeding. However, lesions from TIMP-2(-/-) Apoe(-/-) mice had higher levels of markers associated with plaque vulnerability, including increased macrophage: vascular smooth muscle cell ratios, larger necrotic core areas, reduced collagen contents, increased macrophage proliferation, and apoptosis frequencies, compared with TIMP-1(-/-)Apoe(-/-) and controls. In contrast, TIMP-1(-/-) Apoe(-/-) animals only had a significant reduction in vascular smooth muscle cell content compared with Apoe(-/-) controls. In vitro and in vivo findings implicated heightened monocyte/macrophage invasion in the detrimental effects observed on atherosclerotic plaque composition in TIMP-2(-/-) Apoe(-/-) mice. Moreover, TIMP-2 specifically decreased MMP-14-dependent monocyte/macrophage infiltration into sites of experimentally induced inflammation and established atherosclerotic lesions.
  
  
  CONCLUSIONS
  Our data demonstrate that TIMP-2 plays a greater protective role than TIMP-1 during the pathogenesis of atherosclerosis, in part by suppressing MMP-14-dependent monocyte/macrophage accumulation into plaques.
authors.affiliation: School of Clinical Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
authors.forename: Karina
authors.initials: K
authors.lastname: Di Gregoli
authors.affiliation: School of Clinical Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: George
authors.affiliation: School of Clinical Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Jackson
authors.affiliation: School of Clinical Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
authors.affiliation: School of Clinical Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK jason.l.johnson@bristol.ac.uk.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Johnson
mesh_terms: D000818:Animals; D005260:Female; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009336:Necrosis / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2
keywords: Atherosclerosis; Macrophage; Matrix metalloproteinases; Monocyte; Plaque progression