Activation of protein kinase C delta reduces hepatocellular damage in ischemic preconditioned rat liver.
BACKGROUND
Liver ischemic preconditioning (IPC), pre-exposure of the liver to transient ischemia, has been applied as a useful surgical method to prevent liver ischemia and reperfusion (I/R) injury. Although activation of protein kinase C (PKC), especially novel PKCs, has been known as central signaling responsible for the liver protection of IPC, determination of the involved isozyme in strong protection afforded by IPC has not been elucidated.


METHODS
Rats were subjected to 90 min of partial liver ischemia followed by 3, 6, and 24 h of reperfusion. IPC was induced by 10 min of ischemia after 10 min of reperfusion before sustained ischemia. Rottlerin, a PKC-δ selective inhibitor; PKC-εV1-2 peptide, a selective PKC-ε inhibitor; and 3,7-dimethyl-1-[2-propargyl] xanthine, an adenosine A2 receptor antagonist, were intravenously injected before IPC. N-acetyl-L-cysteine, a strong antioxidant, and Nω-nitro-L-arginine methyl ester, a nonselective nitric oxide synthase inhibitor, were injected intraperitoneally before IPC.


RESULTS
IPC resulted in strong protection against liver I/R injury as evidenced by biochemical and histologic analyses. Inhibition of PKC-δ strongly attenuated the IPC-induced liver protection, whereas PKC-ε inhibition did not exert any effect on IPC-induced protection. Although inhibition of reactive oxygen species, adenosine, and nitric oxide attenuated the beneficial effects of IPC, inhibition of adenosine only attenuated PKC-δ and -ε translocation.


CONCLUSIONS
Our findings suggest that IPC protects against I/R-induced hepatic injury through activation of PKC-δ.
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
Nari
N
Yun
Sun-Mee
SM
Lee
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019194:Ischemic Preconditioning / Q000379:methods*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; C085746:rottlerin; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon
Ischemia and reperfusion; Ischemic preconditioning; Liver; Protein kinase C