Abstract 12542: A Single-Dose Recombinant Glutathione S-Transferase P1-1 Improves Cardiac Function Post Myocardial Infarction in Rats
Acute myocardial infarction (MI) is associated with inflammatory cascades that go on to harm cardiomyocytes even after the acute event. Cellular tumor necrosis factor (TNF)-α signaling occurs via TNF-α receptor-associated factor 2 (TRAF2)-dependent activation of the mitogen-activated protein kinase (MAPK) proinflammatory cascade. Glutathione S-transferase P1-1 (GSTP1-1), primarily involved in oxidative stress responses, has been implicated in the prevention of TNF-α-associated apoptosis through interaction with TRAF2, and ameliorating inflammation by suppressing MAPK activity. We hypothesized that antagonizing the inflammation cascade by GSTP-1 might improve cardiac function following MI. MI was induced by left coronary artery ligation in 60 rats; and recombinant GSTP-1 was administrated at 1 mg/kg body weight 2 h thereafter. Controls received vehicle. Cardiac function was assessed using magnet resonance imaging (MRI) at 1 and 21 days post-MI. Myocardial tissue was processed for molecular and histological analyses. RT-PCR revealed significantly decreased myocardial tissue mRNA levels of interleukin (IL)-1β and -2 (p<0.02; p<0.01) in GSTP-1-treated rats compared to controls. Western blotting also indicated downregulated inflammatory c-Jun-N-terminal kinase and p38 and downregulated pro-apoptotic caspase 3 and 9 tissue protein levels following GSTP-1 treatment versus controls (p<0.01). TUNEL assay showed decreased number of apoptotic cardiomyocytes in GSTP1-treated rats compared to controls (p<0.001). Masson's Trichrome staining clearly indicated an increase in infarct wall thickness and reduced collagen in GSTP1-treated animals when compared to controls (p<0.003). MRI indicated that GSTP1-treatment significantly improved ejection fraction (EF) and cardiac index and lowered end-diastolic and end-systolic volumes compared to controls (p<0.01). In conclusion, single-dose recombinant GSTP-1 could serve as a novel treatment modality post MI that prevents the development of reduced EF heart failure.
- © 2011 by American Heart Association, Inc.