Involvement of the ornithine decarboxylase/polyamine system in precondition-induced cardioprotection through an interaction with PKC in rat hearts.
Polyamines (putrescine, spermidine, and spermine) play an essential role in cell growth, differentiation, and apoptosis. Protein kinase C (PKC) stimulates polyamine biosynthesis through the induction of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis. Activation of PKC mediates ischemic preconditioning to reduce necrosis and apoptosis in intact hearts and in isolated culture cardiomyocytes. In this study, we examined whether the ODC/polyamine system is involved in the ischemic preconditioning signaling pathway and whether this system interacts with PKC in preconditioning-induced cardioprotection. Hearts were preconditioned with three cycles of 5-min ischemia and 5-min reflow, which caused an increase of ODC expression and spermidine, spermine, and total polyamine pool levels. alpha-Difluoromethylornithine (DFMO) and ethylglyoxal bis (guanylhydrazone) (EGBG) inhibited the key enzymes involved in polyamine biosynthesis, and abolished the preconditioning-induced reduction in infarct size and improvement in postischemic heart contractility function. They also increased cell apoptosis extent and aggravated myocardium ultrastructure damage. Inhibition also attenuated the preconditioning-induced translocation and activation of the PKC-delta, -epsilon isoforms from the cytosol to the particulate. Conversely, activation of PKC by phorbol 12-myristate 13-acetate (PMA) upregulated the ODC/polyamine system, whereas the PKC inhibitor chelerythrine (Che) downregulated the ODC/polyamine system. These findings suggest that upregulation of the polyamine synthesis metabolism occurs in response to preconditioning and mediates preconditioning-induced cardioprotection. The ODC/polyamine system and PKC signals may "cross-talk" in preconditioned hearts such that inhibiting one pathway leads to a reduction in the activity of the other pathway and vice versa.
Zhao
Ya-Jun
YJ
Department of Pathophysiology, Harbin Medical University, 150086, Harbin, China.
Zhang
Wei-Hua
WH
Xu
Chang-Qing
CQ
Li
Hong-Zhu
HZ
Wang
Li-Na
LN
Li
Hong
H
Sun
Yi-Hua
YH
Lin
Yan
Y
Han
Li-Ping
LP
Zhang
Li
L
Tian
Yie
Y
Wang
Rui
R
Yang
Bao-Feng
BF
Li
Wei-Min
WM
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control*; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D011073:Polyamines / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D011073:Polyamines; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate