Formation of protein kinase Cε-Lck signaling modules confers cardioprotection
Peipei Ping, … , William M. Pierce, Roberto Bolli
Peipei Ping, … , William M. Pierce, Roberto Bolli
Published February 15, 2002
Citation Information: J Clin Invest. 2002;109(4):499-507. https://doi.org/10.1172/JCI13200.
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Article

Formation of protein kinase Cε-Lck signaling modules confers cardioprotection

Abstract

The ε isoform of protein kinase C (PKCε) is a member of the PKC family of serine/threonine kinases and plays a critical role in protection against ischemic injury in multiple organs. Functional proteomic analyses of PKCε signaling show that this isozyme forms multiprotein complexes in the heart; however, the precise signaling mechanisms whereby PKCε orchestrates cardioprotection are poorly understood. Here we report that Lck, a member of the Src family of tyrosine kinases, forms a functional signaling module with PKCε. In cardiac cells, PKCε interacts with, phosphorylates, and activates Lck. In vivo studies showed that cardioprotection elicited either by cardiac-specific transgenic activation of PKCε or by ischemic preconditioning enhances the formation of PKCε-Lck modules. Disruption of these modules, via ablation of the Lck gene, abrogated the infarct-sparing effects of these two forms of cardioprotection, indicating that the formation of PKCε-Lck signaling modules is required for the manifestation of a cardioprotective phenotype. These findings demonstrate, for the first time to our knowledge, that the assembly of a module (PKCε-Lck) is an obligatory step in the signal transduction that results in a specific phenotype. Thus, PKCε-Lck modules may serve as novel therapeutic targets for the prevention of ischemic injury.

Authors

Peipei Ping, Changxu Song, Jun Zhang, Yiru Guo, Xinan Cao, Richard C.X. Li, Wenjian Wu, Thomas M. Vondriska, Jason M. Pass, Xian-Liang Tang, William M. Pierce, Roberto Bolli

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Ablation of the Lck gene abrogates ischemic preconditioning (PC) and PKC...
Ablation of the Lck gene abrogates ischemic preconditioning (PC) and PKCε-induced cardioprotection. (a) Mice underwent a 30-minute coronary occlusion followed by a 4-hour reperfusion. After postmortem perfusion, the nonischemic portion of the left ventricle was stained dark blue and the viable tissue within the region at risk bright red, whereas the infarcted tissue was stained light yellow. Illustrated are representative examples of infarcts observed in wild-type mice subjected to sham surgery (controls), wild-type mice subjected to ischemic PC, PKCε transgenic mice, and double mutant mice expressing active PKCε with ablation of the Lck gene. Myocardial infarction was markedly reduced in the wild-type preconditioned mouse and in the PKCε mouse not subjected to ishcemic PC. However, in the PKCε−Lck–/– mouse, the extent of infarction was similar to the control mouse. (b) Quantitative analysis of infarct size in wild-type and Lck–/– mice. Infarct size was similar in wild-type and Lck–/– non-preconditioned mice, indicating that basal LCK activity does not modulate the severity of ishcemia/reperfusion injury. When mice were subjected to ischemic PC, infarct size was reduced in wild-type but not in Lck–/– mice, indicating that Lck is an obligatory signaling component in the genesis of late ischemic PC. *P < 0.05 vs. group I. (c) Quantitative analysis of infarct size in wild-type, PKCε transgenic, and PKCε-Lck–/– mice. Activation of PKCε reduced infarct size to 31.0% ± 3.6% of the risk region. This protective effect of PKCε transgenesis was absent in PKCε-Lck–/– mice, indicating that PKCε-induced cardioprotection requires Lck. *P < 0.05 vs. group I. Data are mean ± SEM.