title: Fibrosis in endstage human heart failure: severe changes in collagen metabolism and MMP/TIMP profiles.
abstract: OBJECTIVE
  We studied fibrosis, collagen metabolism, MMPs/TIMPs and cytokine expression in various forms of human heart failure (HF) by quantitative immunofluorescent microscopy, Western blot, zymography, RT-PCR and in situ hybridization. In explanted human hearts with HF due to either dilated (DCM, n=6) or ischemic (ICM-BZ-borderzone, ICM-RZ-remote zone, n=7) or inflammatory (myocarditis, MYO, n=6) cardiomyopathy and 8 controls MMP2, 8, 9, 19, and TIMP1, 2, 3, 4 as well as procollagens I and III (PINP, PIIINP), mature collagen III (IIINTP) and the cross-linked collagen I degradation product (ICTP) were measured.
  
  
  RESULTS
  In comparison with controls, MMPs and TIMPs were significantly upregulated ranging (from highest to lowest) from ICM-BZ, DCM, ICM-RZ, MYO for all MMPs with the exception of MMP9 (highest in DCM), and for TIMPs from ICM-BZ, ICM-RZ, DCM and MYO. MMP2 and 9 were activated in all groups. The TIMP/MMP ratio was 1.3 for control, 1.9 in ICM-BZ (TIMP>MMP) and lowered to 1.0 in the other groups. Collagen I/collagen III ratio correlated significantly with the decrease in LVEDP. PINP was higher than ICTP in all groups. PIIINP elevation was present in DCM and ICM-RZ and IIINTP was up to 4-fold augmented in all groups. Fibrosin mRNA was upregulated in ICM-BZ, activin A in MYO but FGF1 and FGF2 remained unchanged. ANP mRNA was increased in all groups.
  
  
  CONCLUSIONS
  Although different degrees of severity of collagen metabolism, MMP/TIMP imbalance and cytokine expression in diverse forms of HF are present, the end product is collagen deposition. These findings suggest multiple mechanisms acting alone or in concert in fibrosis development in HF.
authors.affiliation: Core Lab for Molecular and Cellular Biology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Polyakova
authors.forename: Ivo
authors.initials: I
authors.lastname: Loeffler
authors.forename: Stefan
authors.initials: S
authors.lastname: Hein
authors.forename: Shigeru
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Izabela
authors.initials: I
authors.lastname: Piotrowska
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dammer
authors.forename: Juha
authors.initials: J
authors.lastname: Risteli
authors.forename: Jutta
authors.initials: J
authors.lastname: Schaper
authors.forename: Sawa
authors.initials: S
authors.lastname: Kostin
mesh_terms: D000328:Adult; D024042:Collagen Type I / Q000378:metabolism*; D024061:Collagen Type III / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; C088390:TIMP3 protein, human; C522361:MMP2 protein, human; C488762:MMP8 protein, human