Abstract 413: PTEN Knockdown Induces Cardioprotection In Mouse Hearts.
PTEN (phosphatase and tensin homologue deleted on chromosome ten) is a protein phosphatase which negatively regulates the survival protein kinase Akt activity by dephosphorylating phosphatidylinositol–3,4,5-triphosphate. We have reported that brief ischemia results in down-regulation of PTEN in isolated hearts, associated with increased functional recovery and decreased apoptosis after subsequent prolonged ischemia-reperfusion. Here we hypothesize that PTEN knockdown induces cardioprotection in a murine myocardial infarction model. Temporally regulated cardiac-specific PTEN deficient mice were generated by crossing PTENloxP/loxP mice with MHC-MerCreMer+/+mice, expressing a tamoxifen-inducible Cre recombinase protein fused to two mutant estrogen-receptor ligand-binding domains (MerCre-Mer) under the control of the α-myosin heavy chain (MHC) promoter. PTEN deletion was induced by intra-peritoneal injection of tamoxifen before experiments in the experimental mice (PTENloxP/+;MHC-MerCreMer+/−) and confirmed by Western blot analysis. Littermates with the same genotype were treated with vehicle as controls. No change in PTEN levels occurred in control mice. Ischemia and reperfusion were induced by occluding and re-opening the left coronary artery. Wildtype mice were subjected to 30 min of ischemia (I-30) and 120 min of reperfusion (R-120) with or without preceding ischemic preconditioning (IPC), which consisted of I-10/R-5. Conditional PTEN deficient mice (PTD) and littermate controls (CON) were exposed to I-30/R-120. At the end of experiment, infarct size was assessed by triphenyltetrazolium chloride staining. IPC and PTEN deletion significantly reduced infarct size in the heart after I/R when compared with their respective controls (no IPC/IPC = 45.9 ± 2.7/16.6 ± 3.8, p<0.01; CON/PTD = 43.9 ± 2.0/20.0 ± 5.1, p<0.01). Moreover, when wildtype mice were treated with the specific PTEN inhibitor VO-OHpic, followed by I-30/R-120, VO-OHpic increased cardiac functional recovery and limited infarct size. Therefore, PTEN deletion generated IPC-like cardioprotection and PTEN inhibition may provide a novel therapeutic approach against ischemia and reperfusion injury.