PMID- 15598866
OWN - NLM
STAT- MEDLINE
DCOM- 20050322
LR  - 20200930
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 288
IP  - 1
DP  - 2005 Jan
TI  - Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: 
      effects of exogenous MMP inhibition.
PG  - H149-58
AB  - Alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs 
      (TIMPs) have been implicated in adverse left ventricular (LV) remodeling after 
      myocardial infarction (MI). However, the direct mechanistic role of TIMPs in the 
      post-MI remodeling process has not been completely established. The goal of this 
      project was to define the effects of altering endogenous MMP inhibitory control 
      through combined genetic and pharmacological approaches on post-MI remodeling in 
      mice. This study examined the effects of MMP inhibition (MMPi) with PD-166793 (30 
      mg.kg(-1).day(-1)) on LV geometry and function (conductance volumetry) after MI 
      in wild-type (WT) mice and mice deficient in the TIMP-1 gene [TIMP-1 knockout 
      (TIMP1-KO)]. At 3 days after MI (coronary ligation), mice were randomized into 
      four groups: WT-MI/MMPi (n = 10), TIMP1-KO-MI/MMPi (n = 10), WT-MI (n = 22), and 
      TIMP1-KO-MI (n = 23). LV end-diastolic volume (EDV) and ejection fraction were 
      determined 14 days after MI. Age-matched WT (n = 20) and TIMP1-KO (n = 28) mice 
      served as reference controls. LVEDV was similar under control conditions in WT 
      and TIMP1-KO mice (36 +/- 2 and 40 +/- 2 microl, respectively) but was greater in 
      TIMP1-KO-MI than in WT-MI mice (48 +/- 2 vs. 61 +/- 5 microl, P < 0.05). LVEDV 
      was reduced from MI-only values in WT-MI/MMPi and TIMP1-KO-MI/MMPi mice (42 +/- 2 
      and 36 +/- 2 microl, respectively, P < 0.05) but was reduced to the greatest 
      degree in TIMP1-KO mice (P < 0.05). LV ejection fraction was reduced in both 
      groups after MI and increased in TIMP1-KO-MI/MMPi, but not in WT-MI/MMPi, mice. 
      These unique results demonstrated that myocardial TIMP-1 plays a regulatory role 
      in post-MI remodeling and that the accelerated myocardial remodeling induced by 
      TIMP-1 gene deletion can be pharmacologically "rescued" by MMP inhibition. These 
      results define the importance of local endogenous control of MMP activity with 
      respect to regulating LV structure and function after MI.
FAU - Ikonomidis, John S
AU  - Ikonomidis JS
AD  - Division of Cardiothoracic Surgery, Medical University of South Carolina, 114 
      Doughty St., Charleston, SC 29425, USA.
FAU - Hendrick, Jennifer W
AU  - Hendrick JW
FAU - Parkhurst, Andrea M
AU  - Parkhurst AM
FAU - Herron, Amanda R
AU  - Herron AR
FAU - Escobar, Patricia G
AU  - Escobar PG
FAU - Dowdy, Kathryn B
AU  - Dowdy KB
FAU - Stroud, Robert E
AU  - Stroud RE
FAU - Hapke, Elizabeth
AU  - Hapke E
FAU - Zile, Michael R
AU  - Zile MR
FAU - Spinale, Francis G
AU  - Spinale FG
LA  - eng
GR  - HL-59165/HL/NHLBI NIH HHS/United States
GR  - P01 HL-48788-08/HL/NHLBI NIH HHS/United States
GR  - P20 RR-16434/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 ((R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Oligopeptides)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
SB  - IM
MH  - Animals
MH  - Hydroxamic Acids/*pharmacology
MH  - *Matrix Metalloproteinase Inhibitors
MH  - Mice
MH  - Mice, Knockout
MH  - Myocardial Infarction/metabolism/*physiopathology
MH  - Oligopeptides/*pharmacology
MH  - Pressure
MH  - Stroke Volume
MH  - Time Factors
MH  - Tissue Inhibitor of Metalloproteinase-1/*deficiency
MH  - Ventricular Remodeling/*drug effects
EDAT- 2004/12/16 09:00
MHDA- 2005/03/23 09:00
CRDT- 2004/12/16 09:00
PHST- 2004/12/16 09:00 [pubmed]
PHST- 2005/03/23 09:00 [medline]
PHST- 2004/12/16 09:00 [entrez]
AID - 288/1/H149 [pii]
AID - 10.1152/ajpheart.00370.2004 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H149-58. doi: 
      10.1152/ajpheart.00370.2004.