Protein kinase C epsilon-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 (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.
Vondriska
T M
TM
Department of Physiology, Division of Cardiology, University of Louisville, Louisville, KY, USA.
Zhang
J
J
Song
C
C
Tang
X L
XL
Cao
X
X
Baines
C P
CP
Pass
J M
JM
Wang
S
S
Bolli
R
R
Ping
P
P
D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005982:Glutathione Transferase / Q000235:genetics; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D046912:Multiprotein Complexes; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D046911:Macromolecular Substances; D046912:Multiprotein Complexes; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D005982:Glutathione Transferase; C497256:Prkce protein, mouse; D019061:src-Family Kinases; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon