Roles of Tyrosine Kinase and Protein Kinase C in Infarct Size Limitation by Repetitive Ischemic Preconditioning in the Rat

Tanno, Masaya; Tsuchida, Akihito; Nozawa, Yukinaga; Matsumoto, Tomoaki; Hasegawa, Tomohiko; Miura, Tetsuji; Shimamoto, Kazuaki

doi:10.1097/00005344-200003000-00001

Cited by 60 publications

(25 citation statements)

References 35 publications

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“…In fact, a recent study by Darling et al (10) showed that elevation of phosphoAkt levels by postconditioning was detected in transmural samples but not in viable subepicardial samples from rabbit hearts. However, the findings that inhibitors of GSK-3␤ reduced infarct size in this and earlier studies (13,37,38) support the notion that elevation of phospho-GSK-3␤ level by EPO and/or PC, leading to suppression of its activity, is a mechanism, but not simply the result, of cardioprotection.…”

Section: Discussionsupporting

confidence: 85%

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Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3β

Nishihara¹,

Miura²,

Miki³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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103

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. Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3␤. Am J Physiol Heart Circ Physiol 291: H748 -H755, 2006. First published March 24, 2006 doi:10.1152/ajpheart.00837.2005.-The aim of this study was to determine whether erythropoietin (EPO) affords additional cardioprotection to the preconditioned myocardium by enhanced phosphorylation of Akt, STAT3, or glycogen synthase kinase-3␤ (GSK-3␤). Preconditioning (PC) with 5-min ischemia/5-min reperfusion and EPO (5,000 U/kg iv) reduced infarct size (as % of area at risk, %IS/AR) after 20-min ischemia in rat hearts in situ from 56.5 Ϯ 1.8% to 25.2 Ϯ 2.1% and to 36.2 Ϯ 2.8%, respectively. PC-induced protection was significantly inhibited by a protein kinase C inhibitor, chelerythrine (5 mg/kg), and slightly blunted by a phosphatidylinositol-3-kinase inhibitor, wortmannin (15 g/kg). The opposite pattern of inhibition was observed for EPO-induced protection. The combination of PC and EPO further reduced %IS/AR to 8.9 Ϯ 1.9%, and this protection was inhibited by chelerythrine and wortmannin. The additive effects of PC and EPO on infarct size were mirrored by their effects on the level of phosphorylated GSK-3␤ at 5 min after reperfusion but not their effects on the level of phospho-Akt or phospho-STAT3. To mimic phosphorylation-induced inhibition of GSK-3␤ activity, SB-216763 (SB), a GSK-3␤ inhibitor, was administered before ischemia or 5 min before reperfusion. Infarct size was significantly reduced by preischemic injection (%IS/AR ϭ 40.4 Ϯ 2.2% by 0.6 mg/kg SB and 34.0 Ϯ 1.8% by 1.2 mg/kg SB) and also by prereperfusion injection (%IS/AR ϭ 32.0 Ϯ 2.0% by 1.2 mg/kg SB). These results suggest that EPO and PC afford additive infarct size-limiting effects by additive phosphorylation of GSK-3␤ at the time of reperfusion by Akt-dependent and -independent mechanisms. infarct size; phosphatidylinositol-3-kinase; protein kinase C; Akt HUMAN RECOMBINANT ERYTHROPOIETIN (EPO) has been used for decades as a standard therapy for renal anemia. However, recent studies have shown that EPO has potent cell-protective effects in various tissues, including myocardium, in addition to its effect on erythropoiesis (5-7, 12, 16, 25, 26, 33-35, 43). The presence of the EPO receptor in cardiomyocytes has been indicated in , and administration of EPO before or at the time of ischemia has been shown to reduce necrosis, apoptosis, and ventricular dysfunction after ischemia-reperfusion (6,7,12,16,25,(33)(34)(35)43). These features of EPO-induced cardioprotection are similar to those of ischemic preconditioning (PC). Furthermore, it is interesting to note that there are overlaps in signaling pathways provoked by activated EPO receptors and PC: phosphatidylinositol-3-kinase (PI3K)-Akt pathway, ERK pathway, and STAT-mediated pathway (1, 3, 13, 16 -18, 21, 30, 34 -39, 43). However, it is not clear which signaling molecule primarily determines the level of cardioprotection against infarction. It is also unclear whether sign...

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Section: Discussionsupporting

confidence: 85%

“…Surgical preparation was essentially the same as in our previous studies using rats (31,37). In brief, male Sprague-Dawley rats weighing 260 -350 g were anesthetized with pentobarbital sodium (40 mg/kg ip), intubated, and mechanically ventilated with a Harvard Respirator (model 683, Harvard Apparatus, South Natick, MA).…”

Section: Surgical Preparationmentioning

confidence: 99%

Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3β

Nishihara¹,

Miura²,

Miki³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

103

101

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“…L-NAME administered at reperfusion handily blocked the infarct-sparing effect of one cycle of IPC. We also tried L-NAME against three cycles of IPC, a more robust preconditioning stimulus (46). L-NAME still blocked protection (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cardioprotective PKG-independent NO signaling at reperfusion

Cohen

Yang²,

Liu³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Cell models of ischemic preconditioning (IPC) indicate nitric oxide (NO) is involved in protection accruing during reoxygenation but disagree whether it acts through PKG. Using a more relevant intact heart model, we studied isolated rabbit hearts subjected to 30-min coronary artery occlusion/120-min reperfusion. We previously found protection from PKG activator 8-(4-chlorophenylthio)-guanosine 3=,5=-cyclic monophosphate (CPT-cGMP) at reperfusion was blocked by A 2b adenosine receptor (A2bAR), ERK, or phosphatidylinositol 3-kinase (PI3-kinase) blockers. In this investigation A 2bAR agonist BAY 60-6583 or CPT-cGMP at reperfusion reduced infarction comparably to IPC. Their protection was abrogated by N -nitro-L-arginine methyl ester (L-NAME), suggesting a PKG-independent NO synthase in IPC's mediator pathway downstream of PKG and A 2bAR. NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) at reperfusion also protected. This protection was not blocked by PI3-kinase inhibitor wortmannin or ERK antagonist PD-98059, suggesting NO acted downstream of these kinases. Protection from SNAP was not affected by mitochondrial ATP-sensitive K ϩ channel closer 5-hydroxydecanoate, PKC antagonist chelerythrine, reactive oxygen species scavenger N-2-mercaptopropionylglycine, or soluble guanylyl cyclase antagonist 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Absence of ODQ effect indicated NO was acting independently of PKG. BAY 58-2667, a soluble guanylyl cyclase activator, was protective, and L-NAME blocked its infarct-sparing effect, indicating a second signaling event dependent on NO generation but independent of PKG. SB216763, a blocker of glycogen synthase kinase-3␤ (GSK-3␤), decreased infarct size, and its infarct-sparing effect was not affected by L-NAME, suggesting GSK-3␤ acted downstream or independently of NO. Hence, NO signaling occurs in IPC's mediator pathway downstream of Akt and ERK, and its protection is independent of PKG. myocardial infarction; N -nitro-L-arginine methyl ester; nitric oxide; protein kinase G; preconditioning; reperfusion injury; S-nitroso-Nacetyl-D,L-penicillamine ISCHEMIC PRECONDITIONING (IPC) and postconditioning protect the heart through signal transduction pathways that are very similar to each other. Insight into IPC's signaling pathway has revealed a number of feasible strategies for conferring protection that are just beginning to be explored in the clinical setting (19,31,37). Unfortunately, there is still much about the protective mechanism and its signaling pathway that remains unknown. Over the past decade we have attempted to map the signal transduction steps in our rabbit heart model and have paid particular attention to the relative position of the signaling elements. Our strategy has focused on stimulation of the pathway at some intermediate point, such as PKC, with phorbol ester and then pharmacologically blocking another known element. If the protection is lost, then the blocked step must have been downstream of the stimulated one (12). The signaling of IPC can be been di...

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“…Several studies report that the protection of IPC can be blocked by tyrosine kinase antagonists, either by themselves (3,9,22) or in combination with PKC inhibitors (10,35,39). Could EGFR be the tyrosine kinase in question?…”

Section: Discussionmentioning

confidence: 99%

ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases

Krieg¹,

Qin²,

McIntosh³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

121

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Roles of Tyrosine Kinase and Protein Kinase C in Infarct Size Limitation by Repetitive Ischemic Preconditioning in the Rat

Cited by 60 publications

References 35 publications

Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3β

Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3β

Cardioprotective PKG-independent NO signaling at reperfusion

ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases

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