Protein Kinase C e–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 e (PKCe) 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 PKCe in a conscious rabbit model of nitric oxide (NO)-induced late preconditioning. Our data demonstrate that PKCe and Src can form functional signaling modules in vitro: PKCe interacts with Src; the association with PKCe activates Src; and adult cardiac cells receiving recombinant adenoviruses encoding PKCe exhibit increased Src activity. Furthermore, our results show that NO-induced late preconditioning involved PKCe-Src module formation and enhanced the enzymatic activity of PKCe-associated Src. Inhibition of PKC blocked cardioprotection, module formation, and PKCe-associated Src activity, providing direct evidence for a functional role of the PKCe-Src module in the orchestration of NO-induced cardioprotection in conscious rabbits. (Circ Res. 2001;88:1306-1313.)