© 1999 American Heart Association, Inc.
Original Contribution |
Isoform-Selective Activation of Protein Kinase C by Nitric Oxide in the Heart of Conscious Rabbits
A Signaling Mechanism for Both Nitric Oxide–Induced and Ischemia-Induced Preconditioning
From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky.
Correspondence to Peipei Ping, PhD, 511 S Floyd St, MDR Bldg, Room 526, Departments of Physiology and Biophysics, Medicine/Division of Cardiology, University of Louisville, Louisville, KY 40202. E-mail ping{at}ntr.net
Abstract—Although
isoform-selective translocation of protein kinase C (PKC) 
appears
to play an important role in the late phase of ischemic
preconditioning (PC), the mechanism(s) responsible for such
translocation remains unclear. Furthermore, the signaling pathway that
leads to the development of late PC after exogenous administration of
NO in the absence of ischemia (NO donor–induced late PC) is
unknown. In the present study we tested the hypothesis that NO
activates PKC and that this is the mechanism for the
development of both ischemia-induced and NO donor–induced late
PC. A total of 95 chronically instrumented, conscious rabbits were
used. In rabbits subjected to ischemic PC (six 4-minute
occlusion/4-minute reperfusion cycles), administration of the NO
synthase inhibitor
N
-nitro-L-arginine (group
III), at doses previously shown to block the development of late PC,
completely blocked the ischemic PC–induced translocation of
PKC but not of PKC
, indicating that increased formation of NO is
an essential mechanism whereby brief ischemia activates
the isoform of PKC. Conversely, a translocation of PKC and -
quantitatively similar to that induced by ischemic PC could be
reproduced pharmacologically with the administration of 2 structurally
unrelated NO donors, diethylenetriamine/NO (DETA/NO) and
S-nitroso-N-acetylpenicillamine (SNAP),
at doses previously shown to elicit a late PC effect. The particulate
fraction of PKC increased from 35±2% of total in the control group
(group I) to 60±1% after ischemic PC (group II)
(P<0.05), to 54±2% after SNAP (group IV)
(P<0.05) and to 52±2% after DETA/NO (group V)
(P<0.05). The particulate fraction of PKC rose from
66±5% in the control group to 86±3% after ischemic PC
(P<0.05), to 88±2% after SNAP
(P<0.05) and to 85±1% after DETA/NO
(P<0.05). Neither ischemic PC nor NO donors had
any appreciable effect on the subcellular distribution of PKC
,
-ß1, -ß2, -
, -
, -µ, or -
/
; on total PKC activity; or
on the subcellular distribution of total PKC activity. Thus, the
effects of SNAP and DETA/NO on PKC closely resembled those of
ischemic PC. The DETA/NO–induced translocation of PKC (but
not that of PKC) was completely prevented by the administration of
the PKC inhibitor chelerythrine at a dose of 5 mg/kg (group
VI) (particulate fraction of PKC, 38±4% of total,
P<0.05 versus group V; particulate fraction of PKC,
79±2% of total). The same dose of chelerythrine completely prevented
the DETA/NO–induced late PC effect against both myocardial stunning
(groups VII through X) and myocardial infarction (groups XI through
XV), indicating that NO donors induce late PC by activating PKC and
that among the 10 isozymes of PKC expressed in the rabbit heart, the
isotype is specifically involved in the development of this form of
pharmacological PC. In all groups examined (groups I through VI), the
changes in the subcellular distribution of PKC protein were
associated with parallel changes in PKC isoform–selective activity,
whereas total PKC activity was not significantly altered. Taken
together, the results provide direct evidence that isoform-selective
activation of PKC is a critical step in the signaling pathway
whereby NO initiates the development of a late PC effect both after an
ischemic stimulus (endogenous NO) and after
treatment with NO-releasing agents (exogenous NO). To our knowledge,
this is also the first report that NO can activate PKC in the
heart. The finding that NO can promote isoform-specific activation of
PKC identifies a new biological function of this radical and a new
mechanism in the signaling cascade of ischemic PC and may also
have important implications for other
pathophysiological conditions in which NO is
involved and for nitrate therapy.
Key Words: diethylenetriamine • nitric oxide • S-nitroso-N-acetylpenicillamine • N-nitro-L-arginine • protein kinase C isoform • translocation
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