Abstract 16719: Withaferin a Attenuates Myocardial Ischemia/ Reperfusion Injury via Mitochondrial Death Cascade Blockade in an AMPK Dependent Manner

Objective: Withaferin A (WFA) impedes cancer metastasis by exerting potent anti-invasive activity and anti-oxidative, anti-inflammatory properties. However, whether WFA attenuates myocardial ischemia/reperfusion (MI/R) injury remains unknown. Methods and Results: WT and AMPK DN (dominant negative AMPKα2 overexpression) mice were subjected to 30 minutes MI and 3 hours R, and treated with WFA (1mg/kg IP, 1.5 hours before LAD coronary artery ligation). WFA administration improved cardiac function, evidenced by increased dp/dtmax 26.4±3.7%, dp/dtmin 24.7±4.8%, and decreased LVEDP 22.6±4.8% in WT after MI/R. WFA treatment reduced cardiac infarct size 28.4±3.1%, decreased apoptosis 34.6±3.2%, and decreased caspase-3 activity 32.1±4.1% post MI/R in WT after MI/R. Next, we attempted to dissect the mechanisms underlying WFA effects. WFA suppressed caspase-9 activity and increased the Bcl-2/Bax ratio (an indicator of mitochondrial death) after MI/R (P<0.05). WFA (125nM) suppressed caspase-9 activity, increased Bcl2...