Inhibition of apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion injury in the mouse.
J Am Heart Assoc
; 1(5): e002360, 2012 Oct.
Article
em En
| MEDLINE
| ID: mdl-23316291
ABSTRACT
BACKGROUND:
Despite the clear advantages of reperfusion in acute myocardial infarction, part of the myocardium is injured during reperfusion by reactive oxygen species. Reactive oxygen species activate apoptosis signal-regulating kinase-1, a key mediator in cell death. We hypothesized that inhibition of apoptosis signal-regulating kinase-1 at the time of reperfusion would protect the heart from ischemia-reperfusion injury. METHODS ANDRESULTS:
Male CD1 mice underwent transient coronary artery ligation (30 minutes) followed by reperfusion or underwent sham surgery (n=10 to 12 per group). A selective small-molecule inhibitor of apoptosis signal-regulating kinase-1 (GS-459679) was given immediately after reperfusion (10 or 30 mg/kg IP). Infarct size was measured early (at 24 hours, in a subgroup of mice) by triphenyl tetrazolium chloride staining and late (at 7 days) by Masson's trichrome staining for fibrosis. Apoptosis was assessed by measurement of caspase-3 activity and by determination of DNA fragmentation in cardiomyocytes bordering the infarct. Transthoracic echocardiography was performed before surgery and then at 24 hours and 7 days later. Treatment with GS-459679 at reperfusion led to a significant dose-related reduction in infarct size (31% for 10 mg/kg [P<0.001 versus vehicle] and 60% for 30 mg/kg [P<0.001 versus vehicle]), inhibition of apoptotic cell death, and preservation of left ventricular dimension and systolic function at both 24 hours and 7 days.CONCLUSIONS:
Inhibition of apoptosis signal-regulating kinase-1 at the time of reperfusion limits infarct size and preserves left ventricular function in a model of acute myocardial infarction in the mouse.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão Miocárdica
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MAP Quinase Quinase Quinase 5
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Infarto do Miocárdio
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article