Inducible and cardiac specific PTEN inactivation protects ischemia/reperfusion injury

Abstract

PTEN is a dual lipid and protein phosphatase that antagonizes PI3K as well as other signaling pathways and regulates cellular survival and growth. However, its potential role in cardiac ischemia/reperfusion injury remains unknown. We established a transgenic mouse model with inducible and cardiac specific deletion of Pten gene ( Pten CKO ) in adult heart via tamoxifen dependent Cre-loxP mediated DNA recombination. 3 weeks after tamoxifen induced PTEN inactivation, elevated PI3K activity was observed in the Pten CKO hearts as determined from downstream AKT signaling. No significant differences in cardiac function as well as chamber size were observed between Pten CKO and Control animals based on echocardiography. In response to 30 min ischemia followed by 120 min reperfusion in Langendorff preparations, Pten CKO hearts developed significantly better function recovery than Control animals. At 60 min post reperfusion, the recovery of LVDP reached 77.9% of pre-ischemia basal in Pten CKO hearts vs 44.2% of Control ( p < 0.01). Consistent with the observed functional improvement, TTC staining revealed a significant reduction in infarct size in Pten CKO hearts compared with Control (24.2% vs 39.7%, p < 0.05). Pten CKO hearts had significantly fewer apoptosis positive cardiomyocytes after I/R injury as identified by TUNEL staining. Furthermore, ERK activity and BCL-2 expression were not affected at basal but became significantly higher after ischemia/reperfusion in Pten CKO hearts. These data indicate that PTEN may play a role in ischemia/reperfusion injury by inhibiting anti-apoptotic survival signals. Inhibiting PTEN may serve as a potential approach to exert cardiac protection against ischemia reperfusion injury.