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PTEN Activity Is Modulated During Ischemia and Reperfusion

Involvement in the Induction and Decay of Preconditioning

From the Vascular Biology Program, Institute for Cell Engineering (Z.C., G.L.S.); the Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology (G.L.S.); and the McKusick-Nathans Institute of Genetic Medicine (Z.C., G.L.S.), The Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Zheqing Cai, Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N Broadway, Ste 671, Baltimore, MD 21205. E-mail czheqin1{at}jhmi.edu

Ischemic preconditioning (IPC), a brief period of ischemia and reperfusion (I/R), generates profound but transient protection against a subsequent prolonged ischemic episode. The serine-threonine kinase Akt has been shown to mediate IPC, and Akt activation is negatively regulated by the phosphatase PTEN, but whether PTEN activity is modulated by IPC has not been investigated. When isolated, perfused rat hearts were subjected to an IPC stimulus consisting of 15-minute ischemia and 30-minute reperfusion (I-15/R-30), PTEN protein levels and activity were decreased, and levels of phospho-AKT were increased, relative to nonischemic hearts. Hearts subjected to IPC demonstrated improved recovery of cardiac function when subsequently subjected to I-30/R-45 as compared with hearts subjected to I-30/R-45 without prior IPC. When hearts were subjected to I-15 followed by R-30, R-60, or R-120, PTEN reaccumulated gradually and its activity was restored. Phospho-Akt levels at R-120 were decreased and these hearts were no longer protected against injury when subjected to I-30/R-45. Wortmannin administration during reperfusion blocked Akt activation and PTEN reaccumulation. In ischemic hearts, PTEN was rapidly degraded. Pretreatment with proteasome inhibitor MG132 blocked ischemia-induced degradation of PTEN and blocked IPC. Reperfusion following I-15 induced oxidation of the remaining PTEN, leading to Akt activation. Perfusion of H₂O₂ was sufficient to induce Akt activation. Thus, loss of PTEN activity leads to induction of IPC and feedback mechanisms designed to ensure that Akt activation is transient are responsible for decay of IPC.

Key Words: Akt • apoptosis • ischemia • PTEN

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