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Myocardial protection from ischemia/reperfusion injury by targeted deletion of matrix metalloproteinase-9.

Abstract：

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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Romanic AM,Harrison SM,Bao W,Burns-Kurtis CL,Pickering S,Gu J,Grau E,Mao J,Sathe GM,Ohlstein EH,Yue TL

doi

10.1016/s0008-6363(02)00254-7

subject

Has Abstract

pub_date

2002-06-01 00:00:00

pages

549-58

issue

eissn

0008-6363

issn

1755-3245

pii

S0008636302002547

journal_volume

pub_type

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Myocardial protection from ischemia/reperfusion injury by targeted deletion of matrix metalloproteinase-9.