Inhibition of apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion injury in the mouse.

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 AND RESULTS:

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.

• Authors: Stefano Toldo, David G Breckenridge, Eleonora Mezzaroma, Benjamin W Van Tassell, John Shryock, Harsha Kannan, Dillon Phan, Grant Budas, Daniela Farkas, Edward Lesnefsky, Norbert Voelkel, Antonio Abbate
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 1 Issue 5 Pg. e002360 (Oct 2012) ISSN: 2047-9980 [Electronic] England
• PMID: 23316291 (Publication Type: Journal Article)

Chemical References

• MAP Kinase Kinase Kinase 5

Topics

• Animals
• DNA Fragmentation (drug effects)
• Echocardiography
• MAP Kinase Kinase Kinase 5 (antagonists & inhibitors)
• Male
• Mice
• Models, Animal
• Myocardial Infarction (enzymology, pathology, prevention & control)
• Myocardial Reperfusion Injury (enzymology, pathology, prevention & control)
• Myocytes, Cardiac (enzymology, pathology)