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-Ak--eNOS signaling module in cardiac protection
1 Department of Physiology and Medicine/Cardiology, UCLA, Los Angeles, CA, USA
2 Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: peipeiping{at}earthlink.net.
Cardiac protective signaling networks have been shown to involve protein kinase C epsilon (PKC
). However, the molecular mechanisms by which PKC interacts with other members of these networks to form task-specific modules remain unknown. Among 93 different PKC-associated proteins identified to date, Akt and endothelial nitric oxide synthase (eNOS) are of importance due to their independent abilities to promote cell survival and prevent cell death. However, the simultaneous association of PKC, Akt and eNOS has never been examined, and in particular, the formation of a module containing these three proteins, and the role of such a module in the regulation of nitric oxide (NO) production and cardiac protection, is unknown. Accordingly, the present study was undertaken to determine whether these molecules form a signaling module and thereby
play a collective role in cardiac signaling. Using both recombinant proteins in vitro and PKC transgenic mouse hearts, we demonstrate that: (i) PKC, Akt and eNOS interact and form signaling modules both in vitro and in the mouse heart; activation of either PKC or Akt enhances the formation of PKC-Akt-eNOS signaling modules; (ii) PKC directly phosphorylates and enhances activation of Akt in vitro, and PKC activation increases both phosphorylation and activation of Akt in PKC transgenic mouse hearts; (iii) PKC directly phosphorylates eNOS in vitro, and this phosphorylation enhances eNOS activity; activation of PKC in vivo increased phosphorylation of eNOS at Ser1177, indicating eNOS activation. This study characterizes, for the first time, the physical, as well as functional, coupling of PKC, Akt, and eNOS in the heart, and implicates these PKC-Akt-eNOS signaling modules as critical signaling elements during PKC-induced cardiac protection.
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