Cross-talk between pka and akt protects endothelial cells from apoptosis in the late ischemic preconditioning

Alessandro Bellis, Diletta Castaldo, Valentina Trimarco, Maria Gaia Monti, Pierpaolo Chivasso, Junichi Sadoshima, Bruno Trimarco, Carmine Morisco

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37 Scopus citations


OBJECTIVE-: The aim of this study was to explore the molecular mechanisms involved in late preconditioning-induced cell protection in endothelial cells. METHODS AND RESULTS-: Preconditioning (PC) was induced by exposing bovine aortic endothelial cells (BAECs) to 3 cycles of 15 minutes of hypoxia followed by 15 minutes of reoxygenation. A 12-hour period of hypoxia induced cell death in 60% of BAECs (48±5% apoptosis, 12±4% necrosis). Early and late PC decreased hypoxia-induced apoptotic (25±5% and 28±4%, respectively) and necrotic (6±3%, and 8±2%, respectively) cell death. Consistently, hypoxia-induced caspase-3 cleavage was reduced by PC. Pretreatment with H89 (protein kinase A [PKA] inhibitor), LY294002 (phosphatidyl-inositol-3-kinase [PI3K] inhibitor), and N-acetyl-cysteine (antioxidant) abrogated late PC-induced cell protection, whereas inhibition of protein kinase C by Go6983, and of nitric oxide synthesis by L-NAME,1400W and bovine eNOS siRNA did not. In addition, in early and late PC, PKA physically interacted with the phosphorylated form of Akt, suggesting that PKA is required for Akt phosphorylation. Expression of PKA and Akt dominant negative mutants inhibited ischemic late PC-induced protection, indicating that these kinases play a key role in late PC-mediated cell protection. CONCLUSIONS-: Late ischemic PC protects BAECs against hypoxia through PKA- and PI3K-dependent activation of Akt.

Original languageEnglish (US)
Pages (from-to)1207-1212
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number8
StatePublished - Aug 2009

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine


  • Caspase-3
  • Cell protection
  • Hypoxia
  • Nitric oxide
  • Phosphatidyl-inositol-3-kinase


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