Translocation of PKC, Protein Phosphatase Inhibition and Preconditioning of Rabbit Cardiomyocytes

Armstrong, Stephen; Hoover, Donald B.; Delacey, M.; Ganote, Charles E.

doi:10.1006/jmcc.1996.0138

Cited by 49 publications

(24 citation statements)

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“…Once these events have taken place, administration of PKC inhibitors has no effect on the development of the PC phenomenon. The results obtained in our model of late PC differ from those obtained in previous studies in models of early PC, which have shown that the activation of PKC is not necessary to trigger the protection in isolated rabbit myocytes (48) and in isolated rabbit hearts (49). In one of these studies (49), Yang et al demonstrated that the infarct-sparing effect was blocked when the PKC inhibitor staurosporine was present during the second (sustained) ischemic insult but not when it was present during or immediately after the initial ischemic PC stimulus, indicating that the activity of PKC is required to mediate the protection but not to put the heart into a preconditioned state.…”

Section: Discussioncontrasting

confidence: 99%

“…Because of the extensive differences between these previous studies (48,49) and the present investigation (early PC versus late PC; PC against lethal injury versus PC against stunning; different experimental preparations), a direct comparison is not possible. Because the cellular and molecular mechanisms responsible for the two phases of ischemic PC are likely to be different, it is conceivable that the PKC-mediated signaling events underlying early and late PC may also be different.…”

Section: Discussionmentioning

confidence: 79%

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Direct evidence that protein kinase C plays an essential role in the development of late preconditioning against myocardial stunning in conscious rabbits and that epsilon is the isoform involved.

Qiu¹,

Ping²,

Tang³

et al. 1998

J. Clin. Invest.

153

181

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Brief ischemic episodes confer marked protection against myocardial stunning 1-3 d later (late preconditioning [PC] against stunning). The mechanism of this powerful protective effect is poorly understood. Although protein kinase C (PKC) has been implicated in PC against infarction, it is unknown whether it triggers late PC against stunning. In addition, the entire PKC hypothesis of ischemic PC remains controversial, possibly because the effects of PKC inhibitors on PC protection have not been correlated with their effects on PKC activity and/or translocation in vivo. Thus, conscious rabbits underwent a sequence of six 4-min coronary occlusion (O)/4-min reperfusion (R) cycles for three consecutive days (days 1, 2, and 3). In the control group (group I, n ϭ 7), the recovery of systolic wall thickening after the six O/R cycles was markedly improved on days 2 and 3 compared with day 1, indicating the development of late PC against stunning. Administration of the PKC inhibitor chelerythrine at a dose of 5 mg/kg before the first O on day 1 (group II, n ϭ 10) abrogated the late PC effect against stunning, whereas a 10-fold lower dose (0.5 mg/kg; group III, n ϭ 7) did not. Administration of 5 mg/kg of chelerythrine 10 min after the sixth reperfusion on day 1 (group IV, n ϭ 6) failed to block late PC against stunning. When rabbits were given 5 mg/kg of chelerythrine in the absence of O/R (group V, n ϭ 5), the severity of myocardial stunning 24 h later was not modified. Pretreatment with phorbol 12-myristate 13-acetate (4 g/kg) on day 1 without ischemia (group VI, n ϭ 11) induced late PC against stunning on day 2 and the magnitude of this effect was equivalent to that observed after ischemic PC. In vehicle-treated rabbits (group VIII, n ϭ 5), the six O/R cycles caused translocation of PKC isoforms ⑀ and from the cytosolic to the particulate fraction without significant changes in total PKC activity, in the subcellular distribution of total PKC activity, or in the subcellular distribution of the ␣ , ␤ 1 , ␤ 2 , ␥ , ␦ , , , , and isoforms. The higher dose of chelerythrine (5 mg/kg; group X, n ϭ 5) prevented the translocation of both PKC ⑀ and induced by ischemic PC, whereas the lower dose (0.5 mg/kg; group XI, n ϭ 5) prevented the translocation of PKC but not that of ⑀ , indicating that the activation of ⑀ is necessary for late PC to occur whereas that of is not. To our knowledge, this is the first demonstration that a PKC inhibitor actually prevents the translocation of PKC induced by ischemic PC in vivo, and that this inhibition of PKC translocation results in loss of PC protection. Taken together, the results demonstrate that the mechanism of late PC against myocardial stunning in conscious rabbits involves a PKCmediated signaling pathway, and implicate ⑀ as the specific PKC isoform responsible for the development of this cardioprotective phenomenon.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 79%

Direct evidence that protein kinase C plays an essential role in the development of late preconditioning against myocardial stunning in conscious rabbits and that epsilon is the isoform involved.

Qiu¹,

Ping²,

Tang³

et al. 1998

J. Clin. Invest.

153

181

View full text Add to dashboard Cite

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“…Preconditioning occurs in 2 phases: an early phase, also known as acute preconditioning, in which protection lasts up to 1-2 h following preconditioning, and a second phase, known as the second window of protection, in which protection reappears 24-72 h following preconditioning. Although a variety of mediators and effectors have been proposed to be essential for conferring preconditioning, including the adenosine receptor [2] , protein kanase C [3] , and the ATP-sensitive K + channel [4] . The importance of PKC to ischemic preconditioning has been shown in a variety of studies in whole heart and isolated ventricular cardiocytes [5] .…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C-dependent activation of P44/42 mitogen-activated protein kinase and heat shock protein 70 in signal transduction during hepatocyte ischemic preconditioning

Gao

Shan²,

Pan³

et al. 2004

WJG

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AIM:To investigate the significance of protein kinase C (PKC), P44/42 mitogen-activated protein kinase (MAPKs) and heat shock protein (HSP)70 signal transduction during hepatocyte ischemic preconditioning. METHODS:In this study we used an in vitro ischemic preconditioning (IP) model for hepatocytes and an in vivo model for rat liver to investigate the significance of protein kinase C (PKC), P44/42 mitogen-activated protein kinase (P44/42 MAPKs) and heat shock protein 70 (HSP70) signal transduction in IP. Through a normal liver cell hypoxic preconditioning (HP) model in which cultured normal liver cells were subjected to 3 cycles of 5 min of incubation under hypoxic conditions followed by 5 min of reoxygenation and subsequently exposed to hypoxia and reoxygenation for 6 h and 9 h respectively. PKC inhibitor, activator and MEK inhibitor were utilized to analyze the phosphorylation of PKC, the expression of P44/42 MAPKs and HSP70. Viability and cellular ultrastructure were also observed. By using rat liver as an in vivo model of liver preconditioning (3 cycles of 10-min occlusion and 10-min reperfusion), in vivo phosphorylation of PKC and P44/42MAPKs, HSP70 expression were further analyzed. AST/ALT concentration, cellular structure and ultrastruture were also observed. All the data were statistically analyzed. RESULTS:Similar results were obtained in both in vivo and in vitro IP models. Compared with the control without IP (or HP), the phosphorylation of PKC and P44/42 MAPKs and the expression of HSP70 were obviously increased in IP (or HP) treated model in which cytoprotection could be found. The effects of preconditioning were mimicked by stimulating PKC with 4β phorobol-12-myristate13-acetate (PMA). Conversely, inhibiting PKC with chelerythrine abolished the protection given by preconditioning. PD98059, inhibitor of MEK (the upstream kinase of P44/42MAPKs), also reverted the cytoprotection exerted by preconditioning. CONCLUSION:The results demonstrate that preconditioning induces a rapid activation of P44/42MAPKs and PKC activation plays a pivotal role in the activation of P44/42 MAPKs pathway that participates in the preservation of liver cells. HSP expression is regulated by signals in PKC dependent P44/ 42 MAPKs pathway.Gao Y, Shan YQ, Pan MX, Wang Y, Tang LJ, Li H, Zhang Z. Protein kinase C-dependent activation of P44/42 mitogenactivated protein kinase and heat shock protein 70 in signal transduction during hepatocyte ischemic preconditioning.

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“…Studies in cultured rat neonatal cardiomyocytes have identified Cx43 phosphorylation sites for several kinases, including protein kinase (PK) A, PKC, PKG, and mitogen-activated protein (MAP) kinase (18)(19)(20). It is believed that activation of PKC plays a major role in PC (21). PKC is involved in signaling complexes with many proteins, among them Cx43.…”

Section: Introductionmentioning

confidence: 99%

Ischemic Preconditioning Protects Against Gap Junctional Uncoupling in Cardiac Myofibroblasts

Sundset

Cooper

Mikalsen

et al. 2004

Cell Communication & Adhesion

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Translocation of PKC, Protein Phosphatase Inhibition and Preconditioning of Rabbit Cardiomyocytes

Cited by 49 publications

References 0 publications

Direct evidence that protein kinase C plays an essential role in the development of late preconditioning against myocardial stunning in conscious rabbits and that epsilon is the isoform involved.

Direct evidence that protein kinase C plays an essential role in the development of late preconditioning against myocardial stunning in conscious rabbits and that epsilon is the isoform involved.

Protein kinase C-dependent activation of P44/42 mitogen-activated protein kinase and heat shock protein 70 in signal transduction during hepatocyte ischemic preconditioning

Ischemic Preconditioning Protects Against Gap Junctional Uncoupling in Cardiac Myofibroblasts

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