title: PKCepsilon inhibits the hyperglycemia-induced apoptosis signal in adult rat ventricular myocytes.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Nephrology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA. malhotas@umdnj.edu
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.forename: Barinder P S
authors.initials: BP
authors.lastname: Kang
authors.forename: Sayed
authors.initials: S
authors.lastname: Hashmi
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Meggs
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon
references.citation: Circ Res. 1999 Apr 16;84(7):752-62
references.pmid: 10205143
references.citation: J Biol Chem. 1994 Apr 8;269(14):10444-50
references.pmid: 8144628
references.citation: Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1625-34
references.pmid: 11959624
references.citation: Circ Res. 2003 May 2;92(8):873-80
references.pmid: 12663490
references.citation: Diabetes. 2001 Jun;50(6):1414-24
references.pmid: 11375343
references.citation: J Clin Invest. 1998 Apr 1;101(7):1326-42
references.pmid: 9525975
references.citation: J Biol Chem. 1996 Oct 4;271(40):24962-6
references.pmid: 8798776
references.citation: Am J Physiol Renal Physiol. 2003 Nov;285(5):F1013-24
references.pmid: 12876069
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12798-803
references.pmid: 10536002
references.citation: Circ Res. 2000 Dec 8;87(12):1123-32
references.pmid: 11110769
references.citation: Circ Res. 1999 Jan 8-22;84(1):34-42
references.pmid: 9915772
references.citation: Diabetes. 2001 Aug;50(8):1918-26
references.pmid: 11473056
references.citation: Circ Res. 2000 Jun 9;86(11):1173-9
references.pmid: 10850970
references.citation: Circ Res. 1997 Dec;81(6):1027-33
references.pmid: 9400384
references.citation: J Neurosci. 1995 Nov;15(11):7158-67
references.pmid: 7472470
references.citation: Science. 1995 Apr 14;268(5208):247-51
references.pmid: 7716516
references.citation: Circ Res. 2002 Mar 8;90(4):390-7
references.pmid: 11884367
references.citation: J Mol Cell Cardiol. 1997 Mar;29(3):859-70
references.pmid: 9152847