Sustained in vivo cardiac protection by a rationally designed peptide that causes epsilon protein kinase C translocation.
Brief periods of cardiac ischemia trigger protection from subsequent prolonged ischemia (preconditioning). epsilon Protein kinase C (epsilonPKC) has been suggested to mediate preconditioning. Here, we describe an epsilonPKC-selective agonist octapeptide, psiepsilon receptor for activated C-kinase (psiepsilonRACK), derived from an epsilonPKC sequence homologous to its anchoring protein, epsilonRACK. Introduction of psiepsilonRACK into isolated cardiomyocytes, or its postnatal expression as a transgene in mouse hearts, increased epsilonPKC translocation and caused cardio-protection from ischemia without any deleterious effects. Our data demonstrate that epsilonPKC activation is required for protection from ischemic insult and suggest that small molecules that mimic this epsilonPKC agonist octapeptide provide a powerful therapeutic approach to protect hearts at risk for ischemia.
Dorn
G W
GW
Department of Medicine, University of Cincinnati, Cincinnati, OH 45167-0590, USA.
Souroujon
M C
MC
Liron
T
T
Chen
C H
CH
Gray
M O
MO
Zhou
H Z
HZ
Csukai
M
M
Wu
G
G
Lorenz
J N
JN
Mochly-Rosen
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000517:prevention & control*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D051381:Rats; D017208:Rats, Wistar; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000627:therapeutic use*
D002316:Cardiotonic Agents; D007527:Isoenzymes; D009842:Oligopeptides; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; C497256:Prkce protein, mouse; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon