© 1999 American Heart Association, Inc.
Integrative Physiology |
Demonstration of Selective Protein Kinase C–Dependent Activation of Src and Lck Tyrosine Kinases During Ischemic Preconditioning in Conscious Rabbits
From the Experimental Research Laboratory (P.P., J.Z., R.C.X.L., B.D., X.-L.T., H.T., Z.B., R.B.), Division of Cardiology and the Department of Physiology and Biophysics (P.P., J.Z., Y.-T.Z., R.C.X.L., Z.B., R.B.), University of Louisville and Jewish Hospital Heart and Lung Institute, Louisville, Ky.
Correspondence to Peipei Ping, PhD, 511 South Floyd St, MDR Bldg, Room 526, University of Louisville, Louisville, KY 40202. E-mail ping{at}ntr.net
Abstract—Src tyrosine kinases
have been shown to mediate cellular responses to stress in noncardiac
cells. However, the effect of myocardial ischemia on Src
tyrosine kinases is unknown. Furthermore, the identity of the tyrosine
kinase(s) involved in the genesis of ischemic preconditioning
(PC) remains obscure. Here, we present the first evidence that
ischemic PC (6 cycles of 4-minute coronary occlusion
and 4-minute reperfusion) induces selective activation of 2 members of
the Src family of tyrosine kinases, Src and Lck, in the heart of
conscious rabbits. The activation of Src in the particulate fraction
was not evident at 5 minutes after ischemic PC but became
apparent at 30 minutes (+119% versus control), whereas the activation
of Lck in the particulate fraction was apparent both at 5 minutes
(+103% versus control) and at 30 minutes (+89%) after
ischemic PC. The activity of the other 5 members of the Src
tyrosine kinases expressed in the rabbit heart (Fyn, Fgr, Yes, Lyn, and
Blk) was not affected by ischemic PC. Ischemic PC had
no effect on the activity of epidermal growth factor receptor kinases,
either at 5 or at 30 minutes. The activation of Src and Lck was
completely abrogated by the tyrosine kinase inhibitor
lavendustin A, given at doses that have previously been shown to block
the protective effect of ischemic PC in this same conscious
rabbit model, suggesting that Src and Lck kinases are essential for the
development of ischemic PC. The activity of the 
isoform of
protein kinase C (PKC) in the particulate fraction increased at 5
minutes (+72%) and at 30 minutes (+67%) after ischemic PC.
Pretreatment with lavendustin A had no effect on the activation of
PKC, whereas pretreatment with the PKC inhibitor
chelerythrine (given at doses that have previously been shown to block
ischemic PC) blocked not only the activation of PKC but also
that of Src and Lck, indicating that Src and Lck are downstream of
PKC in the signaling cascade of ischemic PC. This study
identifies a new component of the signaling mechanism of
ischemic PC. The results support the concept that, in conscious
rabbits, 2 specific members of the Src family of tyrosine kinases, Src
and Lck, play an important role in the genesis of late PC by serving as
downstream elements of PKC-mediated signal transduction.
Key Words: PKC • cardiac signaling • chelerythrine • lavendustin A • myocardial stunning • myocardial infarction
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