title: Elevated serum MMP-9/TIMP-1 ratio in patients with homozygous familial hypercholesterolemia: effects of LDL-apheresis.
abstract: OBJECTIVE
  Matrix degradation within an atherosclerotic plaque is an important pathogenic factor in atherosclerosis, and is largely modulated by the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors (i.e., tissue inhibitor of MMPs [TIMPs]). Familial hypercholesterolemia (FH) is a rare inherited disorder associated with premature coronary heart disease. The aim of the present study was to examine MMP-9 and TIMP-1 on plasma and cellular mRNA levels in homozygous FH patients (n=7) compared with age- and sex-matched heterozygous FH patients (n=6), and with healthy subjects (n=7), and to test whether once-weekly LDL-apheresis (three consecutive sessions) of homozygous FH patients show short-term effects on these variables.
  
  
  RESULTS
  The main findings were that (i) Compared to healthy control subjects, homozygous FH patients have significantly higher serum levels of MMP-9 and lower levels of TIMP-1, and consequently significantly higher MMP-9/TIMP-1 ratio, potentially reflecting higher MMP-9 activity. (ii) Peripheral blood mononuclear cells (PBMC) isolated from FH homozygotes have significantly higher mRNA levels of MMP-9 compared to cells from heterozygotes. (iii) TNFα-stimulated PBMC from FH homozygotes released borderline-significantly more MMP-9 than cells from heterozygotes and healthy controls. (iv) LDL-apheresis (one day before treatment versus fifteen days later, on the day after the weekly treatment) had no significant short-term effect on any of the MMP-9 and TIMP-1 variables measured in serum and cells.
  
  
  CONCLUSIONS
  The data may suggest that homozygous FH patients have an enhanced matrix degrading potential as compared with heterozygous FH patients and healthy controls, potentially contributing to the increased cardiovascular risk observed in these patients.
authors.affiliation: Lipid Clinic, Oslo University Hospital Rikshospitalet, and Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway. marit.s.nenseter@rr-research.no
authors.forename: Marit S
authors.initials: MS
authors.lastname: Nenseter
authors.forename: Ingunn
authors.initials: I
authors.lastname: Narverud
authors.forename: Asgeir
authors.initials: A
authors.lastname: Græsdal
authors.forename: Martin P
authors.initials: MP
authors.lastname: Bogsrud
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Leiv
authors.initials: L
authors.lastname: Ose
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Holven
mesh_terms: D000293:Adolescent; D000328:Adult; D050197:Atherosclerosis / Q000276:immunology; D001781:Blood Component Removal; D002318:Cardiovascular Diseases / Q000235:genetics; D002648:Child; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000235:genetics; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000097:blood* / Q000235:genetics; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D055815:Young Adult
chemical_list: D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9