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...
Background-Myocardial ischemia and reperfusion-induced tissue injury involve a robust inflammatory response, but the proximal events in reperfusion injury remain incompletely defined. Toll-like receptor 4 (TLR4) is a proximal signaling receptor in innate immune responses to lipopolysaccharide of Gram-negative pathogens. TLR4 is also expressed in the heart and vasculature, but a role for TLR4 in the myocardial response to injury separate from microbial pathogens has not been examined. This study assessed the role of TLR4 in myocardial infarction and inflammation in a murine model of ischemia-reperfusion injury. Methods and Results-Myocardial ischemia-reperfusion (MIR) was performed on 2 strains of TLR4-deficient mice (C57/BL10 ScCr and C3H/HeJ) and controls (C57/BL10 ScSn and C3H/OuJ). Mice were subjected to 1 hour of coronary ligation, followed by 24 hours of reperfusion. TLR4-deficient mice sustained significantly smaller infarctions compared with control mice given similar areas at risk. Fewer neutrophils infiltrated the myocardium of TLR4-deficient Cr mice after MIR, indicated by less myeloperoxidase activity and fewer CD45/GR1-positive cells. The myocardium of TLR4-deficient Cr mice contained fewer lipid peroxides and less complement deposition compared with control mice after MIR. Serum levels of interleukin-12, interferon-␥, and endotoxin were not increased after ischemia-reperfusion. Neutrophil trafficking in the peritoneum was similar in all strains after injection of thioglycollate. Conclusions-TLR4-deficient mice sustain smaller infarctions and exhibit less inflammation after myocardial ischemiareperfusion injury. The data suggest that in addition to its role in innate immune responses, TLR4 serves a proinflammatory role in murine myocardial ischemia-reperfusion injury.
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