Background-A potential mechanism for left ventricular (LV) remodeling after myocardial infarction (MI) is activation of the matrix metalloproteinases (MMPs). This study examined the effects of MMP inhibition (MMPi) on regional LV geometry and MMP levels after MI. Methods and Results-In pigs instrumented with radiopaque markers to measure regional myocardial geometry, MI was created by ligating the obtuse marginals of the circumflex artery. In the first study, pigs were randomized to MMPi (nϭ7; PD166793, 20 mg · kg Ϫ1 · d Ϫ1 ) or MI only (nϭ7) at 5 days after MI, and measurements were performed at 2 weeks. Regional MI areas were equivalent at randomization and were increased in the MI-only group at 2 weeks after MI compared with the MMPi group. In the second study, pigs randomized to MMPi (nϭ9) or MI only (nϭ8) were serially followed up for 8 weeks. At 8 weeks after MI, LV end-diastolic dimension was lower with MMPi than in the MI-only group (4.7Ϯ0.1 versus 5.1Ϯ0.1 cm, PϽ0.05). Regional MI area was reduced with MMPi at 8 weeks after MI (1.3Ϯ0.1 versus 1.7Ϯ0.1 cm 2 , PϽ0.05). MMPi reduced ex vivo MMP proteolytic activity. In the MI region, membrane-type MMP levels were normalized and levels of the endogenous tissue inhibitor of MMPs (TIMP-1) were increased compared with normal levels with MMPi. These effects were not observed in the MI-only group. Conclusions-MMPi

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-Matrix metalloproteinases (MMPs) contribute to left ventricular remodeling after myocardial infarction (MI). Specific causative roles of particular MMPs, however, remain unclear. MMP-7 is abundant in cardiomyocytes and macrophages, but MMP-7 function after MI has not been defined. Methods and Results-Wild-type (WT; nϭ55) and MMP-7-null (MMP-7 Ϫ/Ϫ ; nϭ32) mice underwent permanent coronary artery ligation for 7 days. MI sizes were similar, but survival was greatly improved in MMP-7 Ϫ/Ϫ mice. The survival difference could not be attributed to differences in left ventricular dilation because end-diastolic volumes increased similarly. ECG analysis revealed a prolonged PR interval in WT but not in MMP-7 Ϫ/Ϫ post-MI mice. Post-MI conduction velocity, determined by optically mapping electrical wavefront propagation, decreased to 78Ϯ6% of control for WT and was normalized in MMP-7 Ϫ/Ϫ mice. In WT mice, slower conduction velocity correlated with a 53% reduction in the gap junction protein connexin-43. Direct binding of MMP-7 to connexin-43, determined by surface plasmon resonance technology, occurred in a dose-dependent manner. Connexin-43 processing by MMP-7 was confirmed by in silico and in vitro substrate analyses and MMP-7 infusion induced arrhythmias in vivo. Conclusions-MMP-7 deletion results in improved survival and myocardial conduction patterns after MI. This is the first report to implicate MMP-7 in post-MI remodeling and to demonstrate that connexin-43 is a novel MMP-7 substrate.

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.

No abstract

Background-The direct consequences of a persistently increased myocardial expression of the unique matrix metalloproteinase (MMP) membrane type-1 (MT1-MMP) on myocardial remodeling remained unexplored. Methods and Results-Cardiac-restricted MT1-MMPexp was constructed in mice using the full-length human MT1-MMP gene ligated to the myosin heavy chain promoter, which yielded approximately a 200% increase in MT1-MMP when compared with age/strain-matched wild-type (WT) mice. Left ventricular (LV) function and geometry was assessed by echocardiography in 3-month ("young") WT (nϭ32) and MT1-MMPexp (nϭ20) mice and compared with 14-month ("middle-aged") WT (nϭ58) and MT1-MMPexp (nϭ35) mice. LV end-diastolic volume was similar between the WT and MT1-MMPexp young groups, as was LV ejection fraction. In the middle-aged WT mice, LV end-diastolic volume and ejection fraction was similar to young WT mice. However, in the MT1-MMPexp middle-aged mice, LV end-diastolic volume was Ϸ43% higher and LV ejection fraction 40% lower (both PϽ0.05). Moreover, in the middle-aged MT1-MMPexp mice, myocardial fibrillar collagen increased by nearly 2-fold and was associated with Ϸ3-fold increase in the processing of the profibrotic molecule, latency-associated transforming growth factor binding protein. In a second study, 14-day survival after myocardial infarction was significantly lower in middle-aged MT1-MMPexp mice. Conclusions-Persistently increased myocardial MT1-MMP expression, in and of itself, caused LV remodeling, myocardial fibrosis, dysfunction, and reduced survival after myocardial injury. These findings suggest that MT1-MMP plays a mechanistic role in adverse remodeling within the myocardium. (Circ Heart Fail. 2009;2:351-360.)