Matrix metalloproteinases (MMPs) are postulated to be necessary for neovascularization during wound healing. MMP-9 deletion alters remodeling postmyocardial infarction (post-MI), but whether and to what degree MMP-9 affects neovascularization post-MI is unknown. Neovascularization was evaluated in wild-type (WT; n ϭ 63) and MMP-9 null (n ϭ 55) mice at 7-days post-MI. Despite similar infarct sizes, MMP-9 deletion improved left ventricular function as evaluated by hemodynamic analysis. Blood vessel quantity and quality were evaluated by three independent studies. First, vessel density was increased in the infarct of MMP-9 null mice compared with WT, as quantified by Griffonia (Bandeiraea) simplicifolia lectin I (GSL-I) immunohistochemistry. Second, preexisting vessels, stained in vivo with FITClabeled GSL-I pre-MI, were present in the viable but not MI region. Third, a technetium-99m-labeled peptide (NC100692), which selectively binds to activated ␣v␤3-integrin in angiogenic vessels, was injected into post-MI mice. Relative NC100692 activity in myocardial segments with diminished perfusion (0 -40% nonischemic) was higher in MMP-9 null than in WT mice (383 Ϯ 162% vs. 250 Ϯ 118%, respectively; P ϭ 0.002). The unique finding of this study was that MMP-9 deletion stimulated, rather than impaired, neovascularization in remodeling myocardium. Thus targeted strategies to inhibit MMP-9 early post-MI will likely not impair the angiogenic response. leukocytes; remodeling; imaging REMODELING OF THE LEFT VENTRICLE (LV) postmyocardial infarction (post-MI) evokes changes to both cellular and extracellular matrix components to progressively alter LV structure and function (35). Matrix metalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases that can cleave all components of the extracellular matrix (ECM) and thereby exert influence on LV remodeling. MMPs are elevated after MI, and a cause and effect relationship between MMPs and LV remodeling has been demonstrated through the use of MMP inhibitors and MMP-null mice (23,38,55). In particular, MMP-9 is a 92-kDa gelatinase upregulated acutely post-MI, and MMP-9 gene deletion results in attenuated LV remodeling after MI (6, 22). Thus MMP-9 likely contributes to adverse LV remodeling post-MI.For the purposes of this study, we use neovascularization and angiogenesis interchangeably according to the following previously assigned definition: the sprouting of new vessels at the capillary level (48). MMPs have also demonstrated roles in neovascularization, and MMP inhibition has been postulated to inhibit the angiogenic process (43). Clinical trials with MMP inhibitors, however, have suggested that MMP inhibition may promote, rather than inhibit, neovascularization (2). MMP-9 is a specific MMP that has been implicated in angiogenesis, and the macrophage is one of several cell types that express MMP-9 post-MI (46). The exact role of MMPs, particularly MMP-9, in post-MI neovascularization is not clear. The MMP-9 substrate portfolio is broad and includes both angiogenic a...

This study, for the first time, identified specific differences in cellular and extracellular processes that likely contribute to age-dependent ECM remodeling.

Background-A cause-and-effect relationship exists between matrix metalloproteinase (MMP) induction and left ventricular (LV) remodeling after myocardial infarction (MI). Whether broad-spectrum MMP inhibition is necessary and the timing at which MMP inhibition should be instituted after MI remain unclear. This study examined the effects of MMP-1 and MMP-7-sparing inhibition (sMMPi) on regional and global LV remodeling when instituted before or after MI. Methods and Results-Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to MI only (nϭ11) or sMMPi (PGE-530742, 10 mg/kg PO TID) begun 3 days before MI (nϭ11) or 3 days after MI (nϭ10). Eleven weight-matched noninstrumented pigs served as reference controls. At 10 days after MI, infarct size was similar between groups (47Ϯ3% of the area at risk

Myocardial remodeling after myocardial infarction (MI) is associated with increased levels of the matrix metalloproteinases (MMPs). Levels of two MMP species, MMP-2 and MMP-9, are increased after MI, and transgenic deletion of these MMPs attenuates post-MI left ventricular (LV) remodeling. This study characterized the spatiotemporal patterns of gene promoter induction for MMP-2 and MMP-9 after MI. MI was induced in transgenic mice in which the MMP-2 or MMP-9 promoter sequence was fused to the beta-galactosidase reporter, and reporter level was assayed up to 28 days after MI. Myocardial localization with respect to cellular sources of MMP-2 and MMP-9 promoter induction was examined. After MI, LV diameter increased by 70% (P < 0.05), consistent with LV remodeling. beta-Galactosidase staining in MMP-2 reporter mice was increased by 1 day after MI and increased further to 64 +/- 6% of LV epicardial area by 7 days after MI (P < 0.05). MMP-2 promoter activation occurred in fibroblasts and myofibroblasts in the MI region. In MMP-9 reporter mice, promoter induction was detected after 3 days and peaked at 7 days after MI (53 +/- 6%, P < 0.05) and was colocalized with inflammatory cells at the peri-infarct region. Although MMP-2 promoter activation was similarly distributed in the MI and border regions, activation of the MMP-9 promoter was highest at the border between the MI and remote regions. These unique findings visually demonstrated that activation of the MMP-2 and MMP-9 gene promoters occurs in a distinct spatial relation with reference to the MI region and changes in a characteristic time-dependent manner after MI.

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Background-Whether

Background-The matrix metalloproteinases (MMPs) contribute to regional remodeling after prolonged periods of ischemia and reperfusion (I/R), but specific MMP types activated during this process remain poorly understood. A novel class, the membrane-type MMPs (MT-MMPs), has been identified in the myocardium, but activity of these MMP types has not been assessed in vivo, particularly during I/R. Methods and Results-Pigs (30 kg, nϭ8) were instrumented with microdialysis catheters to measure MT1-MMP activity in both ischemic and nonischemic (remote) myocardium. A validated MT1-MMP fluorogenic substrate was infused through the microdialysis system, and changes in fluorescence were reflective of MT1-MMP activity at steady state, during ischemia (90 minutes), and during reperfusion (120 minutes). At peak ischemia, MT1-MMP activity was increased by Ͼ40% in the ischemic region, with no change in the remote region, which persisted with reperfusion (PϽ0.05). After I/R, MT1-MMP abundance was increased by Ͼ50% (PϽ0.05). Differential centrifugation revealed that the endosomal fraction (which contains subcellular organelles) within the ischemic myocardium was associated with a Ͼ135% increase in MT1-MMP (PϽ0.05). Furthermore, in an isolated left ventricular myocyte model of I/R, hypoxia (simulated ischemia) induced a Ͼ70% increase in MT1-MMP abundance in myocytes, and confocal microscopy revealed MT1-MMP internalization during this time period and reemergence to the membrane with reperfusion. Conclusions-These unique results demonstrate that a specific MMP type, MT1-MMP, is increased in abundance and activity with I/R and is likely attributed, at least in part, to changes in intracellular trafficking.

Discrete myocardial lesions created through the delivery of radiofrequency (RF) energy can expand; however, the mechanisms have not been established. Matrix metalloproteinases (MMPs) play an important role in myocardial remodeling, and MMP activity can be regulated by the tissue inhibitors of the metalloproteinases (TIMPs). This study examined the role of TIMP-1 in postinjury myocardial remodeling. Lesions were created on the left ventricular (LV) epicardium of wild-type (WT, 8-12 wk, 129SVE) and age-matched TIMP-1 gene-deficient (timp-1(-/-)) mice through the delivery of RF current (80 degrees C, 30 s). Heart mass, LV scar volumes, and collagen content were measured at 1 h and 3, 7, and 28 days postinjury (n = 10 each). Age-matched, nonablated mice were used as reference controls (n = 5). Heart mass indexed to tibial length increased in WT and timp-1(-/-) mice but was greater in the timp-1(-/-) mice by 7 days. Scar volumes increased in a time-dependent manner in both groups but were higher in the timp-1(-/-) mice than the WT mice at 7 days (1.48 +/- 0.09 vs. 1.20 +/- 0.11 mm(3).mg(-1).mm, P < 0.05) and remained higher at 28 days. In the remote myocardium, wall thickness was greater and relative collagen content was lower in the timp-1(-/-) mice at 28 days postinjury. Discrete myocardial RF lesions expand in a time-dependent manner associated with myocyte hypertrophy remote to the scar. Moreover, postinjury myocardial remodeling was more extensive with TIMP-1 gene deletion. Thus TIMP-1 either directly or through modulation of MMP activity may regulate myocardial remodeling following infliction of a discrete injury.