Abstract 3301: Myocardial Injury is Attenuated in Akt Knockout Mice After Ischemia-Reperfusion
Many studies have reported that acute Akt activation induces cardioprotection. However, chronic activation of Akt has been shown to cause cardiac hypertrophy and an increase in myocardial injury after ischemia-reperfusion (I/R). To clarify the role of Akt, we examined whether Akt protects the heart and reduces cardiac remodeling following I/R using a knockout mouse model. Wildtype and Akt knockout mice (12 weeks old) were exposed to 30 min of ischemia, followed by 30 days of reperfusion. Before ischemia, Akt knockout mice weighed less than wildtype mice (23.7±0.9 vs. 27.1±0.3 g, n=4, p<0.05), but at the end of the experiment, the difference was no longer present. Moreover, heart weight in Akt knockout mice was significantly less than that in wildtype mice (173±7 vs. 191±4 mg, n=8, p<0.05). We measured cardiac function with a pressure catheter before collecting the heart. Akt knockout mice had significantly better left ventricular developed pressure (95±9 vs. 68±5 mm Hg, n=8, p<0.05) and cardiac contractility (+dp/dt: 5998±641 vs. 3645±414 mm Hg/sec., n=8, p<0.01). Importantly, myocardial infarct size (percentage of infarcted myocardium to area at risk) was decreased in Akt knockout mice (36±3 vs. 50±4 %, n=6, p<0.05). Furthermore, we measured Akt and its downstream protein FOXO3a under basal conditions in the heart by Western blot analysis. Akt was undetectable in Akt knockout mice. Surprisingly, FOXO3a phosphorylation was significantly increased in Akt knockout mice compared with wildtype mice (97±10 vs. 39±7 AU, n=4, p<0.01. Thus, Akt knockout mice showed resistance to I/R injury, with reduced infarct size and improved left ventricular function 30 days after infarction. These results suggest that Akt deletion may induce compensatory downstream responses, and that Akt may not be necessary for protection against I/R injury.