Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction

Merry L. Lindsey, Joseph Gannon, Masanori Aikawa, Frederick J. Schoen, Elena Rabkin, Lori Lopresti-Morrow, Jamie Crawford, Shawn Black, Peter Libby, Peter G. Mitchell, Richard T. Lee

Research output: Contribution to journalArticle

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Abstract

Background - Broad inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling after myocardial infarction (MI). However, it is not clear if selective MMP inhibition strategies will be effective or if MMP inhibition will impair angiogenesis after MI. Methods and Results - We used a selective MMP inhibitor (MMPi) that does not inhibit MMP-1 in rabbits, which, like humans but unlike rodents, express MMP-1 as a major collagenase. On day 1 after MI, rabbits were randomized to receive either inhibitor (n=10) or vehicle (n=8). At 4 weeks after MI, there were no differences in infarct size or collagen fractional area. However, MMPi reduced ventricular dilation. The increase in end-diastolic dimension from day 1 to week 4 was 3.1±0.5 mm for vehicle versus 1.3±0.3 mm for MMPi (P<0.01). The increase in end-systolic dimension was 2.8±0.5 mm for vehicle and 1.3±0.4 mm for MMPi (P<0.05). Furthermore, MMPi reduced infarct wall thinning; the minimal infarct thickness was 0.8±0.1 mm for vehicle and 1.6±0.3 mm for MMPi (P<0.05). Interestingly, the MMPi group had increased numbers of vessels in the subendocardial layer of the infarct; the number of capillaries was increased in the subendocardial layer (46±4 vessels/field versus 17±3 vessels/field for vehicle; P<0.001), and the number of arterioles was also increased (4.0±0.8 vessels/field versus 2.0±0.4 vessels/field for vehicle; P<0.05). Conclusions - MMP inhibition attenuates left ventricular remodeling even when the dominant collagenase MMP-1 is not inhibited; furthermore, this selective MMP inhibition appears to increase rather than decrease neovascularization in the subendocardium.

Original languageEnglish (US)
Pages (from-to)753-758
Number of pages6
JournalCirculation
Volume105
Issue number6
DOIs
StatePublished - Feb 12 2002

Fingerprint

Ventricular Remodeling
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases
Myocardial Infarction
Matrix Metalloproteinase 1
Collagenases
Rabbits
Arterioles
Dilatation
Rodentia
Collagen

Keywords

  • Metalloproteinases
  • Myocardial infarction
  • Remodeling
  • Ventricles

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. / Lindsey, Merry L.; Gannon, Joseph; Aikawa, Masanori; Schoen, Frederick J.; Rabkin, Elena; Lopresti-Morrow, Lori; Crawford, Jamie; Black, Shawn; Libby, Peter; Mitchell, Peter G.; Lee, Richard T.

In: Circulation, Vol. 105, No. 6, 12.02.2002, p. 753-758.

Research output: Contribution to journalArticle

Lindsey, ML, Gannon, J, Aikawa, M, Schoen, FJ, Rabkin, E, Lopresti-Morrow, L, Crawford, J, Black, S, Libby, P, Mitchell, PG & Lee, RT 2002, 'Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction', Circulation, vol. 105, no. 6, pp. 753-758. https://doi.org/10.1161/hc0602.103674
Lindsey, Merry L. ; Gannon, Joseph ; Aikawa, Masanori ; Schoen, Frederick J. ; Rabkin, Elena ; Lopresti-Morrow, Lori ; Crawford, Jamie ; Black, Shawn ; Libby, Peter ; Mitchell, Peter G. ; Lee, Richard T. / Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. In: Circulation. 2002 ; Vol. 105, No. 6. pp. 753-758.
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abstract = "Background - Broad inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling after myocardial infarction (MI). However, it is not clear if selective MMP inhibition strategies will be effective or if MMP inhibition will impair angiogenesis after MI. Methods and Results - We used a selective MMP inhibitor (MMPi) that does not inhibit MMP-1 in rabbits, which, like humans but unlike rodents, express MMP-1 as a major collagenase. On day 1 after MI, rabbits were randomized to receive either inhibitor (n=10) or vehicle (n=8). At 4 weeks after MI, there were no differences in infarct size or collagen fractional area. However, MMPi reduced ventricular dilation. The increase in end-diastolic dimension from day 1 to week 4 was 3.1±0.5 mm for vehicle versus 1.3±0.3 mm for MMPi (P<0.01). The increase in end-systolic dimension was 2.8±0.5 mm for vehicle and 1.3±0.4 mm for MMPi (P<0.05). Furthermore, MMPi reduced infarct wall thinning; the minimal infarct thickness was 0.8±0.1 mm for vehicle and 1.6±0.3 mm for MMPi (P<0.05). Interestingly, the MMPi group had increased numbers of vessels in the subendocardial layer of the infarct; the number of capillaries was increased in the subendocardial layer (46±4 vessels/field versus 17±3 vessels/field for vehicle; P<0.001), and the number of arterioles was also increased (4.0±0.8 vessels/field versus 2.0±0.4 vessels/field for vehicle; P<0.05). Conclusions - MMP inhibition attenuates left ventricular remodeling even when the dominant collagenase MMP-1 is not inhibited; furthermore, this selective MMP inhibition appears to increase rather than decrease neovascularization in the subendocardium.",
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T1 - Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction

AU - Lindsey, Merry L.

AU - Gannon, Joseph

AU - Aikawa, Masanori

AU - Schoen, Frederick J.

AU - Rabkin, Elena

AU - Lopresti-Morrow, Lori

AU - Crawford, Jamie

AU - Black, Shawn

AU - Libby, Peter

AU - Mitchell, Peter G.

AU - Lee, Richard T.

PY - 2002/2/12

Y1 - 2002/2/12

N2 - Background - Broad inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling after myocardial infarction (MI). However, it is not clear if selective MMP inhibition strategies will be effective or if MMP inhibition will impair angiogenesis after MI. Methods and Results - We used a selective MMP inhibitor (MMPi) that does not inhibit MMP-1 in rabbits, which, like humans but unlike rodents, express MMP-1 as a major collagenase. On day 1 after MI, rabbits were randomized to receive either inhibitor (n=10) or vehicle (n=8). At 4 weeks after MI, there were no differences in infarct size or collagen fractional area. However, MMPi reduced ventricular dilation. The increase in end-diastolic dimension from day 1 to week 4 was 3.1±0.5 mm for vehicle versus 1.3±0.3 mm for MMPi (P<0.01). The increase in end-systolic dimension was 2.8±0.5 mm for vehicle and 1.3±0.4 mm for MMPi (P<0.05). Furthermore, MMPi reduced infarct wall thinning; the minimal infarct thickness was 0.8±0.1 mm for vehicle and 1.6±0.3 mm for MMPi (P<0.05). Interestingly, the MMPi group had increased numbers of vessels in the subendocardial layer of the infarct; the number of capillaries was increased in the subendocardial layer (46±4 vessels/field versus 17±3 vessels/field for vehicle; P<0.001), and the number of arterioles was also increased (4.0±0.8 vessels/field versus 2.0±0.4 vessels/field for vehicle; P<0.05). Conclusions - MMP inhibition attenuates left ventricular remodeling even when the dominant collagenase MMP-1 is not inhibited; furthermore, this selective MMP inhibition appears to increase rather than decrease neovascularization in the subendocardium.

AB - Background - Broad inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling after myocardial infarction (MI). However, it is not clear if selective MMP inhibition strategies will be effective or if MMP inhibition will impair angiogenesis after MI. Methods and Results - We used a selective MMP inhibitor (MMPi) that does not inhibit MMP-1 in rabbits, which, like humans but unlike rodents, express MMP-1 as a major collagenase. On day 1 after MI, rabbits were randomized to receive either inhibitor (n=10) or vehicle (n=8). At 4 weeks after MI, there were no differences in infarct size or collagen fractional area. However, MMPi reduced ventricular dilation. The increase in end-diastolic dimension from day 1 to week 4 was 3.1±0.5 mm for vehicle versus 1.3±0.3 mm for MMPi (P<0.01). The increase in end-systolic dimension was 2.8±0.5 mm for vehicle and 1.3±0.4 mm for MMPi (P<0.05). Furthermore, MMPi reduced infarct wall thinning; the minimal infarct thickness was 0.8±0.1 mm for vehicle and 1.6±0.3 mm for MMPi (P<0.05). Interestingly, the MMPi group had increased numbers of vessels in the subendocardial layer of the infarct; the number of capillaries was increased in the subendocardial layer (46±4 vessels/field versus 17±3 vessels/field for vehicle; P<0.001), and the number of arterioles was also increased (4.0±0.8 vessels/field versus 2.0±0.4 vessels/field for vehicle; P<0.05). Conclusions - MMP inhibition attenuates left ventricular remodeling even when the dominant collagenase MMP-1 is not inhibited; furthermore, this selective MMP inhibition appears to increase rather than decrease neovascularization in the subendocardium.

KW - Metalloproteinases

KW - Myocardial infarction

KW - Remodeling

KW - Ventricles

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