IntroductionThe extent of ventricular dilation after a myocardial infarction (MI) depends on the magnitude of the initial ischemic damage as well as the tissue healing process (1, 2). This dynamic pathological process includes the expression and activation of the matrix metalloproteinases (MMPs), which may mediate many of the morphological changes that occur after MI in both infarcted and noninfarcted regions (3-5). Members of the MMP family of enzymes degrade specific extracellular matrix components; clinical and experimental studies have shown that MMP expression and activity increase in both MI (5) and dilated cardiomyopathy (6, 7).Because extracellular matrix deposition and organization play a major role in left ventricular (LV) remodeling, MMP inhibition has emerged as a potential therapeutic strategy for patients at risk for the development of congestive heart failure. Administration of a broad-spectrum MMP inhibitor attenuates LV enlargement in pacing-induced congestive heart failure (8) and in the early period after MI occurs (9). Whether this effect depends on the inhibition of many MMPs, or selective inhibition of MMPs can prevent ventricular dilation remains unexplored. Recently, Heymans et al. reported a decreased incidence of rupture at 4 days after MI in MMP-9-deficient animals, suggesting that MMP-9 may have a specific role in early myocardial healing (10). In this study we evaluated the influence of targeted deletion of the MMP-9 gene on LV remodeling after experimental MI in mice. We performed this study with sibling wild-type (WT) controls after at least six backcrosses to minimize genetic variability. All analyses were blinded to genotype; the animals were studied for 15 days. MethodsAnimals and surgery. We used the progeny of heterozygous breeding pairs of mice with targeted disruption of MMP-9, as described by Vu et al. (11). MMP-9-deficient mice have delayed long-bone growth and development due to delayed angiogenesis and ossification; however, by adulthood, these changes result in only a 10% shortening in the long bones. Animals with an FVB background were backcrossed; our studies used the homozygous MMP-9-deficient and sibling WT offspring of generation six or higher. Offspring were eartagged and coded, with tail DNA samples harvested for genotyping using PCR. For MMP-9, we used a sense oligonucleotide primer (5′-GCA TAC TTG TAC CGC TAT GG -3′) and an antisense primer (5′-TAA CCG GAG GTC CAA ACT GG-3′). For the neomycin cassette, we also used a sense oligonucleotide primer (5′-GAA Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diasto...

Matrix metalloproteinase (MMP)-9, one of the most widely investigated MMPs, regulates pathological remodeling processes that involve inflammation and fibrosis in cardiovascular disease. MMP-9 directly degrades extracellular matrix (ECM) proteins and activates cytokines and chemokines to regulate tissue remodeling. MMP-9 deletion or inhibition has proven overall beneficial in multiple animal models of cardiovascular disease. As such, MMP-9 expression and activity is a common end point measured. MMP-9 cell-specific overexpression, however, has also proven beneficial and highlights the fact that little information is available on the underlying mechanisms of MMP-9 function. In this review, we summarize our current understanding of MMP-9 physiology, including structure, regulation, activation, and downstream effects of increased MMP-9. We discuss MMP-9 roles during inflammation and fibrosis in cardiovascular disease. By concentrating on the substrates of MMP-9 and their roles in cardiovascular disease, we explore the overall function and discuss future directions on the translational potential of MMP-9 based therapies.

Background-Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM-1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion. Methods and Results-Constitutive expression of TNF-␣ and not IL-1␤ was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-␣ in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-␣ in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-␣. Conclusions-Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-␣. We suggest that mast cell-derived TNF-␣ may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophilinduced injury. (Circulation. 1998;98:699-710.)