PMID- 12388270
OWN - NLM
STAT- MEDLINE
DCOM- 20030214
LR  - 20200930
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 284
IP  - 2
DP  - 2003 Feb
TI  - Matrix remodeling in experimental and human heart failure: a possible regulatory 
      role for TIMP-3.
PG  - H626-34
AB  - In the failing heart, an imbalance in matrix metalloproteinases (MMPs) and their 
      biological regulators, the tissue inhibitors of MMPs (TIMPs), may result in 
      cardiac dilatation from matrix degradation. We hypothesized that a reduction of 
      myocardial TIMP-3 is associated with adverse matrix remodeling in both human and 
      experimental heart failure. Cardiomyopathic hamsters at age 15 wk (normal), 25 wk 
      (compensated stage), and 35 wk (overt failure) were compared with age-matched 
      normal controls. MMP activity (gelatinase bioassay) was increased in 
      cardiomyopathic hearts (P = 0.03) and peaked during the transition to overt heart 
      failure. TIMP-3 content (immunoblot) was decreased compared with normal controls 
      (74 +/- 5% at 25 wk, 69 +/- 10% at 35 wk; P = 0.001) and its reduction was 
      associated with increased MMP activity (r = -0.6; P = 0.004). TIMP-1 increased 
      progressively (P = 0.001), whereas TIMP-2, TIMP-4, and MMP protein levels were 
      unchanged. Myocardial collagen (hydroxyproline content) increased with time 
      during the progression to end-stage cardiac failure (P < 0.0001). Collagen 
      synthesis ([(14)C]proline uptake) was elevated in cardiomyopathy at 15 and 25 wk 
      (P < 0.05). The collagen cross-linking ratio (insoluble:soluble collagen) was 
      reduced (P = 0.003) as the left ventricle dilated. By confocal microscopy 
      restricted to viable myocardium, collagen content was reduced (P = 0.04) with 
      fragmentation (P < 0.0001) and thinning (P = 0.003) of perimysial collagen 
      fibers. Similarly, patients with end-stage congestive heart failure (n = 7) 
      compared with nonfailing controls (n = 2) had elevated gelatinase MMP activity (P 
      = 0.02) associated with isolated reductions in TIMP-3 (55 +/- 5% of normal; P = 
      0.003). Reductions of TIMP-3 parallel adverse matrix remodeling in the 
      cardiomyopathic hamster and the failing human heart. TIMP-3 may contribute to the 
      regulation of myocardial remodeling and its reduction may promote a transition 
      from compensated to end-stage congestive heart failure.
FAU - Fedak, Paul W M
AU  - Fedak PW
AD  - Division of Cardiac Surgery, Toronto General Research Institute, University of 
      Toronto, Toronto General Hospital, Ontario, Canada M5B 1W8.
FAU - Altamentova, Svetlana M
AU  - Altamentova SM
FAU - Weisel, Richard D
AU  - Weisel RD
FAU - Nili, Nafiseh
AU  - Nili N
FAU - Ohno, Nobuhisa
AU  - Ohno N
FAU - Verma, Subodh
AU  - Verma S
FAU - Lee, Tsu-Yee J
AU  - Lee TY
FAU - Kiani, Chris
AU  - Kiani C
FAU - Mickle, Donald A G
AU  - Mickle DA
FAU - Strauss, Bradley H
AU  - Strauss BH
FAU - Li, Ren-Ke
AU  - Li RK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20021010
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Tissue Inhibitor of Metalloproteinase-3)
RN  - 9007-34-5 (Collagen)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Animals
MH  - Cardiac Output, Low/*metabolism
MH  - Collagen/metabolism
MH  - Cricetinae
MH  - Extracellular Matrix/*metabolism
MH  - Humans
MH  - Image Processing, Computer-Assisted
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Mesocricetus
MH  - Microscopy, Confocal
MH  - Reference Values
MH  - Tissue Inhibitor of Metalloproteinase-3/*metabolism
EDAT- 2002/10/22 04:00
MHDA- 2003/02/15 04:00
CRDT- 2002/10/22 04:00
PHST- 2002/10/22 04:00 [pubmed]
PHST- 2003/02/15 04:00 [medline]
PHST- 2002/10/22 04:00 [entrez]
AID - 00684.2002 [pii]
AID - 10.1152/ajpheart.00684.2002 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2003 Feb;284(2):H626-34. doi: 
      10.1152/ajpheart.00684.2002. Epub 2002 Oct 10.