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

An essential role for protein kinase C epsilon (PKC epsilon) 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 PKC epsilon in a conscious rabbit model of nitric oxide (NO)-induced late preconditioning. Our data demonstrate that PKC epsilon and Src can form functional signaling modules in vitro: PKC epsilon interacts with Src; the association with PKC epsilon activates Src; and adult cardiac cells receiving recombinant adenoviruses encoding PKC epsilon exhibit increased Src activity. Furthermore, our results show that NO-induced late preconditioning involved PKC epsilon -Src module formation and enhanced the enzymatic activity of PKC epsilon -associated Src. inhibition of PKC blocked cardioprotection, module formation, and PKC epsilon -associated Src activity, providing direct evidence for a functional role of the PKC epsilon -Src module in the orchestration of NO-induced cardioprotection in conscious rabbits.