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PHLPP-1 negatively regulates Akt activity and survival in the heart

Shigeki Miyamoto1, Nicole H Purcell, Jeffrey M Smith

  • 1Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, USA. smiyamoto@ucsd.edu

Circulation Research
|June 26, 2010
PubMed

Insights

PHLPP-1 (PH domain leucine-rich repeat protein phosphatase-1) inhibits Akt signaling in heart cells. Blocking PHLPP-1 enhances Akt activity and provides significant cardioprotection against injury.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cell Signaling

Background:

  • PH domain leucine-rich repeat protein phosphatase-1 (PHLPP-1) dephosphorylates Akt at Ser473, inhibiting Akt signaling in cancer cells.
  • The role of PHLPP-1 in cardiac physiology and cardioprotection remains uninvestigated.

Purpose of the Study:

  • To investigate the role of PHLPP-1 in the heart.
  • To determine if inhibiting PHLPP-1 enhances Akt signaling and provides cardioprotection.

Main Methods:

  • PHLPP-1 knockdown using small interfering RNA in neonatal rat ventricular myocytes (NRVMs) and adult mouse ventricular myocytes (AMVMs).
  • Generation and analysis of PHLPP-1 knockout (KO) mice.
  • Assessment of Akt phosphorylation (p-Akt) at Ser473 and Thr308, Akt catalytic activity, and mitochondrial Akt signaling.
  • Evaluation of cardioprotection against doxorubicin and H2O2-induced injury in vitro.
  • Assessment of infarct size in isolated perfused hearts subjected to ischemia/reperfusion.

Main Results:

  • PHLPP-1 knockdown in NRVMs and AMVMs potentiated Akt phosphorylation at Ser473 and increased Akt catalytic activity.
  • PHLPP-1 knockdown conferred cardioprotection against doxorubicin and H2O2.
  • PHLPP-1 localizes to mitochondria, and its knockdown enhanced mitochondrial Akt signaling and hexokinase-II levels.
  • PHLPP-1 KO mice exhibited potentiated Akt signaling in response to agonists and during ischemia/reperfusion.
  • PHLPP-1 KO hearts showed reduced infarct size following ischemia/reperfusion.

Conclusions:

  • PHLPP-1 acts as an endogenous negative regulator of Akt activity and cell survival in the heart.
  • Inhibition of PHLPP-1 represents a potential therapeutic strategy for enhancing cardioprotection.
Abstract

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