title: 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.
  
  
  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: VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA 23298, USA. stoldo2@vcu.edu
authors: Stefano
authors: S
authors: Toldo
authors: David G
authors: DG
authors: Breckenridge
authors: Eleonora
authors: E
authors: Mezzaroma
authors: Benjamin W
authors: BW
authors: Van Tassell
authors: John
authors: J
authors: Shryock
authors: Harsha
authors: H
authors: Kannan
authors: Dillon
authors: D
authors: Phan
authors: Grant
authors: G
authors: Budas
authors: Daniela
authors: D
authors: Farkas
authors: Edward
authors: E
authors: Lesnefsky
authors: Norbert
authors: N
authors: Voelkel
authors: Antonio
authors: A
authors: Abbate
mesh_terms: D000818:Animals; D053938:DNA Fragmentation / Q000187:drug effects; D004452:Echocardiography; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D023421:Models, Animal; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology
chemical_list: D048848:MAP Kinase Kinase Kinase 5
keywords: apoptosis; inhibitors; ischemia; remodeling; reperfusion