PKCepsilon inhibits the hyperglycemia-induced apoptosis signal in adult rat ventricular myocytes.
Recruitment of the protein kinase C (PKC) family of isozymes is an integral component of the signaling events that direct cardiac phenotype expressed during postnatal development and in response to pathologic stimuli. Hyperglycemia is a potent activating signal for cardiac PKC isozymes and induces the apoptosis program in cardiac muscle cells. To determine whether cardiac PKC isozymes modulate transmission of the hyperglycemia apoptosis signal, we have employed isozyme-specific peptide modulators to selectively inhibit (PKC betaI/betaII, zeta and epsilon) or activate (PKCepsilon). PKC peptides were delivered to primary cultures of serum starved adult rat ventricular myocytes (ARVM), by conjugation to the homeodomain of drosophila antennapedia. As expected, hyperglycemia induced a 35% increase in ARVM apoptosis. Peptide inhibitors of PKC betaI/betaII and zeta blocked transmission of the hyperglycemia apoptosis signal, whereas the isozyme specific inhibitor of PKCepsilon (epsilonV1-2) did not alter the magnitude of glucose-induced ARVM apoptosis. Alternatively, the PKCepsilon translocation activator (psi epsilonRACK) abolished hyperglycemia-induced apoptosis, strongly suggesting a cardioprotective role for PKCepsilon in this system. Therefore, we conclude that cardiac PKC isozymes modulate hyperglycemia-induced apoptosis and activation of cardiac PKCepsilon protects ARVM from the hyperglycemia-induced death signal.
Malhotra
Ashwani
A
Department of Medicine, Division of Nephrology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA. malhotas@umdnj.edu
Kang
Barinder P S
BP
Hashmi
Sayed
S
Meggs
Leonard G
LG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D006943:Hyperglycemia / Q000503:physiopathology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; D007527:Isoenzymes; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon
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