Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform

TY - JOUR

T1 - Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform

AU - Wolfrum, Sebastian

AU - Schneider, Kathrin

AU - Heidbreder, Marc

AU - Nienstedt, Julie

AU - Dominiak, Peter

AU - Dendorfer, Andreas

PY - 2002/8/15

Y1 - 2002/8/15

N2 - 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.

AB - 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.

KW - Adrenergic beta-Antagonists

KW - Alkaloids

KW - Animals

KW - Benzophenanthridines

KW - Bradykinin

KW - Enzyme Activation

KW - Enzyme Inhibitors

KW - Ganglionic Blockers

KW - Hexamethonium

KW - Intestines

KW - Ischemic Preconditioning

KW - Ischemic Preconditioning, Myocardial

KW - Isoenzymes

KW - Male

KW - Myocardial Infarction

KW - Myocardium

KW - Phenanthridines

KW - Protein Kinase C

KW - Random Allocation

KW - Rats

KW - Rats, Wistar

KW - Journal Article

M3 - SCORING: Journal article

C2 - 12160956

VL - 55

SP - 583

EP - 589

JO - CARDIOVASC RES

JF - CARDIOVASC RES

SN - 0008-6363

IS - 3

ER -