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


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.
Lindsey
Merry L
ML
Leducq Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, USA.
Gannon
Joseph
J
Aikawa
Masanori
M
Schoen
Frederick J
FJ
Rabkin
Elena
E
Lopresti-Morrow
Lori
L
Crawford
Jamie
J
Black
Shawn
S
Libby
Peter
P
Mitchell
Peter G
PG
Lee
Richard T
RT
D000818:Animals; D015153:Blotting, Western; D002306:Cardiac Volume / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003327:Coronary Disease / Q000150:complications; D004108:Dilatation, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood; D055768:Halogenated Diphenyl Ethers; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D008026:Ligation; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010647:Phenyl Ethers / Q000008:administration & dosage / Q000097:blood; D011817:Rabbits; D015996:Survival Rate; D020257:Ventricular Remodeling / Q000187:drug effects*
C119912:CP 471,474; D004791:Enzyme Inhibitors; D055768:Halogenated Diphenyl Ethers; D061965:Matrix Metalloproteinase Inhibitors; D010647:Phenyl Ethers; D003094:Collagen