© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Myocardial protection from ischemia/reperfusion injury by targeted deletion of matrix metalloproteinase-9
aDepartment of Cardiovascular Pharmacology, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19046, USA
bDepartment of Comparative Genomics, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
cDepartment of Discovery Genetics, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19046, USA
anne_romanic-1{at}gsk.com
* Corresponding author. Tel.: +1-610-270-4841; fax: +1-610-270-5080
Objective: Matrix metalloproteinase-9 (MMP-9) activity is up regulated in the heart subjected to ischemic insult. Whether increased MMP-9 activity contributes to acute myocardial injury after ischemia–reperfusion remains unknown. To investigate the role of MMP-9 in myocardial infarction, we utilized a MMP-9 knockout mouse. Methods and results: Standard homologous recombination in embryonic stem cells was used to generate a mouse lacking MMP-9. The left anterior descending coronary artery was occluded for 30 min followed by 24 h reperfusion, and the ischemic and infarct sizes were determined. Targeted deletion of MMP-9 protected the heart from no-flow ischemia–reperfusion-induced myocardial injury. The myocardial infarct size was reduced by 17.5% in MMP-9 heterozygotes (+/–) (P<0.01) and 35.4% in MMP-9 knockout (–/–) mice (P<0.01) versus the wild-type (+/+) mice, respectively. Analysis of MMP activity in myocardial extracts by zymography demonstrated that ischemia–reperfusion-induced expression of proMMP-9 and active MMP-9 was reduced by 77.8% (P<0.01) and 69.1% (P<0.001), respectively, in (+/–) mice compared to (+/+) mice, and was absent in (–/–) animals. The expression of TIMP-1, an endogenous inhibitor of MMP-9, was elevated 4.7-fold (P<0.05) and 21.4-fold (P<0.05) in the (+/–) and (–/–) mice, respectively, compared to (+/+) mice. Immunohistochemical analysis revealed that neutrophils were the primary cellular source of MMP-9, and less neutrophils were detected in the ischemic region of the heart following ischemia–reperfusion in (–/–) mice compared to (+/+) mice. Measurement of myeloperoxidase activity, a marker enzyme of neutrophils, demonstrated a 44% reduction in neutrophils infiltrated into the ischemic myocardium in the (–/–) mice compared to the (+/+) mice (P<0.05). Conclusion: These results suggest that MMP-9 plays an important role in ischemia–reperfusion-induced myocardial infarction and MMP-9 could be a target for prevention or treatment of acute ischemic myocardial injury.
KEYWORDS Ischemia; Reperfusion; Infarction; Remodeling; Extracellular matrix
1 Authors contributed equally to this work.
2 Present address: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, USA.
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