Protein kinase C epsilon-Src modules direct signal transduction in nitric oxide-induced cardioprotection: complex formation as a means for cardioprotective signaling

Circ Res. 2001 Jun 22;88(12):1306-13. doi: 10.1161/hh1201.092994.


An essential role for protein kinase C epsilon (PKCepsilon) has been shown in multiple forms of cardioprotection; however, there is a distinct paucity of information concerning the signaling architecture that is responsible for the manifestation of a protective phenotype. We and others have recently shown that signal transduction may proceed via the formation of signaling complexes (Circ Res. 2001;88:59-62). In order to understand if the assembly of multiprotein complexes is the manner by which signaling is conducted in cardioprotection, we designed a series of experiments to characterize the associations of Src tyrosine kinase with PKCepsilon in a conscious rabbit model of nitric oxide (NO)-induced late preconditioning. Our data demonstrate that PKCepsilon and Src can form functional signaling modules in vitro: PKCepsilon interacts with Src; the association with PKCepsilon activates Src; and adult cardiac cells receiving recombinant adenoviruses encoding PKCepsilon exhibit increased Src activity. Furthermore, our results show that NO-induced late preconditioning involved PKCepsilon-Src module formation and enhanced the enzymatic activity of PKCepsilon-associated Src. Inhibition of PKC blocked cardioprotection, module formation, and PKCepsilon-associated Src activity, providing direct evidence for a functional role of the PKCepsilon-Src module in the orchestration of NO-induced cardioprotection in conscious rabbits.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Glutathione Transferase / genetics
  • Ischemic Preconditioning, Myocardial*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Macromolecular Substances
  • Mice
  • Multiprotein Complexes
  • Myocardium / cytology
  • Myocardium / metabolism
  • Nitric Oxide / metabolism*
  • Nitric Oxide / pharmacology
  • Nitric Oxide Donors / pharmacology
  • Nitroso Compounds / pharmacology
  • Protein Binding / physiology
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Kinase C-epsilon
  • Rabbits
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transfection
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*


  • Enzyme Inhibitors
  • Isoenzymes
  • Macromolecular Substances
  • Multiprotein Complexes
  • Nitric Oxide Donors
  • Nitroso Compounds
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • 2,2'-(hydroxynitrosohydrazono)bis-ethanamine
  • Nitric Oxide
  • Glutathione Transferase
  • Prkce protein, mouse
  • src-Family Kinases
  • Protein Kinase C
  • Protein Kinase C-epsilon