Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform.
OBJECTIVE
Myocardial protection can be achieved by brief ischemia-reperfusion of remote organs, a phenomenon described as remote preconditioning (RPC). Since the intracellular mechanisms of RPC are not known, we tested the hypothesis that RPC might activate myocardial PKCepsilon, an essential mediator of classical ischemic preconditioning. Furthermore, we tried to delineate the mechanisms by which RPC is transduced to the heart with respect to the possible contribution of kinins and neuronal reflexes.


METHODS
Anesthetized rats were randomised to undergo either 30 min of waiting (controls) or RPC (brief mesenteric artery occlusion followed by reperfusion) in the absence or presence of chelerythrine (5 mg kg(-1)), a specific PKC inhibitor. Myocardial infarct size was measured by TTC staining after 30 min of coronary artery occlusion followed by 150 min of reperfusion. In separate sets of experiments RPC was performed with or without pretreatment with HOE140, a selective B(2)-antagonist or hexamethonium was used to explore the influence of ganglion blockade on RPC. Translocation of PKCepsilon from cytosol to the particulate fraction was measured by quantitative immunoblotting.


RESULTS
RPC significantly reduced infarct size which was completely blocked by the PKC inhibitor. RPC shifted the ratio between cytosolic and particulate PKCepsilon, an indicator for PKC-activation, from 0.95+/-0.06 in controls to 0.41+/-0.09 (P<0.05), and this effect was abolished by HOE140. Activation of PKCepsilon could not be achieved after pretreatment with HEX (0.69+/-0.06 in HEX vs. 0.78+/-0.06 in HEX+RPC).


CONCLUSIONS
RPC activates myocardial PKCepsilon through a neuronal and bradykinin-dependent pathway. We assume that activation of PKCepsilon is an important step in cardioprotection induced by remote preconditioning.
Wolfrum
Sebastian
S
Institute for Experimental and Clinical Pharmacology and Toxicology, Medical University of Lübeck, Germany. wolfrum@medinf.mu-luebeck.de
Schneider
Kathrin
K
Heidbreder
Marc
M
Nienstedt
Julie
J
Dominiak
Peter
P
Dendorfer
Andreas
A
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005730:Ganglionic Blockers / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D007422:Intestines / Q000098:blood supply*; D019194:Ischemic Preconditioning / Q000379:methods*; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D010617:Phenanthridines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D000319:Adrenergic beta-Antagonists; D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D005730:Ganglionic Blockers; D007527:Isoenzymes; D010617:Phenanthridines; D018738:Hexamethonium; C065679:icatibant; C016299:chelerythrine; D011493:Protein Kinase C; D001920:Bradykinin