British Journal of Anaesthesia

BJA Advance Access published online on September 27, 2007
British Journal of Anaesthesia, doi:10.1093/bja/aem202

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Sevoflurane-induced cardioprotection depends on PKC- activation via production of reactive oxygen species

R. A. Bouwman^1,*, R. J. P. Musters², B. J. van Beek-Harmsen², J. J. de Lange¹, R. R. Lamberts¹, S. A. Loer¹ and C. Boer¹

¹ VU University Medical Center (VUMC), Department of Anaesthesiology, Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
² VU University Medical Center (VUMC), Laboratory for Physiology, Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU), Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands

^* Corresponding author. E-mail: a.bouwman{at}vumc.nl

Accepted for publication April 25, 2007.

	Abstract

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Background: We previously demonstrated the involvement of the Ca²⁺-independent protein kinase C- (PKC-) isoform in sevoflurane-induced cardioprotection against ischaemia and reperfusion (I/R) injury. Since sevoflurane is known to modulate myocardial Ca²⁺-handling directly, in this study we investigated the role of the Ca²⁺-dependent PKC- isoform in sevoflurane-induced cardioprotective signalling in relation to reactive oxygen species (ROS), adenosine triphosphate-sensitive mitochondrial K⁺ (mitoK⁺_ATP) channels, and PKC-.

Methods: Preconditioned (15 min 3.8 vol% sevoflurane) isolated rat right ventricular trabeculae were subjected to I/R, consisting of 40 min superfusion with hypoxic, glucose-free buffer, followed by normoxic glucose-containing buffer for 60 min. After reperfusion, contractile recovery was expressed as percentage of force development before I/R. The role of PKC-, ROS, mitoK⁺_ATP channels, and PKC- was established using the following pharmacological inhibitors: Go6976 (GO; 50 nM), n-(2-mercaptopropionyl)-glycine (MPG; 300 µM), 5-hydroxydecanoic acid sodium (5HD; 100 µM), and rottlerin (ROT; 1 µM).

Results: Preconditioning of trabeculae with sevoflurane improved contractile recovery after I/R [65 (3)% (I/R+SEVO) vs 47 (3)% (I/R); n=8; P<0.05]. This cardioprotective effect was attenuated in trabeculae treated with GO [42 (4)% (I/R+SEVO+GO); P>0.05 vs (I/R)]. In sevoflurane-treated trabeculae, PKC- translocated towards mitochondria, as shown by immunofluorescent co-localization analysis. GO and MPG, but not 5HD or ROT, abolished this translocation.

Conclusions: Sevoflurane improves post-ischaemic contractile recovery via activation of PKC-. ROS production, but not opening of mitoK⁺_ATP channels, precedes PKC- translocation towards mitochondria. This study shows the involvement of Ca²⁺-dependent PKC- in addition to the well-established role of Ca²⁺-independent PKC isoforms in sevoflurane-induced cardioprotection.

Keywords: anaesthetics volatile, sevoflurane; enzymes, protein kinase C; enzymes, signal transduction; heart, cardioprotection; heart, ischaemia; signal transduction

	Introduction

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
Sevoflurane protects the myocardium from ischaemia and reperfusion (I/R) injury by eliciting a protective signal transduction cascade.¹ This cardioprotective signalling cascade relies on the production of reactive oxygen species (ROS), activation of protein kinase C (PKC), and opening of ATP-sensitive mitochondrial K⁺ (mitoK⁺_ATP) channels.^2–4 However, the exact mechanisms and target end-effector proteins of sevoflurane-induced cardioprotection remain to be elucidated.

In preconditioning-related signalling cascades, the Ca²⁺-independent PKC isoforms PKC- and - have been considered most important,^4–7 whereas less evidence exists for the involvement of Ca²⁺-dependent PKC isoforms. Nevertheless, in various cardioprotective signalling cascades, Ca²⁺ has been demonstrated as a central mediator,^8–10 and evidence exists that Ca²⁺-dependent iso-enzymes are activated during ischaemia^{9 11} and other preconditioning stimuli, such as Ca²⁺-induced preconditioning.¹² Interestingly, since volatile anaesthetics profoundly modulate myocardial Ca²⁺-handling,¹³ activation of Ca²⁺-dependent PKC isoforms can be expected, but the exact relationship between Ca²⁺-dependent PKC isoforms and volatile anaesthetic-induced preconditioning has not been established.

In this study, using isolated right ventricular trabeculae of the rat, we investigated whether sevoflurane-induced preconditioning involves activation of the Ca²⁺-dependent PKC isoform, PKC-. We specifically focused on the interaction of PKC- with more established mediators of volatile anaesthetic-induced cardioprotective signalling, that is, ROS and mitoK⁺_ATP channels, and especially the essential Ca²⁺-independent PKC isoform PKC-.¹⁴

	Methods

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Animals and experimental set-up
This study was performed in accordance with the guidelines of the Institutional Animal Care and Use Committee of VU University Medical Center. Our experimental set-up has previously been described in detail.^{14 15} Briefly, male Wistar rats (250–400 g; Harlan, The Netherlands) were anaesthetized with sodium pentobarbital (80 mg kg^–1, i.p., Nembutal^® Sanofi Sante BV). Subsequently, the heart was removed and trabeculae were isolated from the right ventricle (length 2–5 mm, diameter <0.2 mm) under contractile arrest conditions. Trabeculae were mounted in an airtight organ bath, superfused with normal Tyrode buffer consisting of 120 mM NaCl, 1.22 mM MgSO₄·7H₂O, 1.99 mM NaH₂PO₄, 27.0 mM NaHCO₃, 5.0 mM KCl, 1 mM CaCl₂, and 10 mM glucose oxygenated with O₂ 95% and CO₂ 5%. The muscles were then stretched up to 95% of the optimal length determined by the force–length relationship. After stabilization (40 min at 27°C followed by 20 min at 24ºC), the initial developed force of contraction (F_dev,start) and the potentiated force (F_pot,start), as determined by a post-extrasystolic potentiation protocol (PESP), were recorded. PESP determines the contractile reserve of trabeculae by maximally filling the sarcoplasmic reticulum with Ca²⁺.¹⁶ Trabeculae failing to stabilize, spontaneously contracting trabeculae and trabeculae failing to show PESP (F_pot,start) were excluded.

Experimental protocol
Figure 1 (Groups A–E) demonstrates the experimental design for all groups exposed to the preconditioning protocol. Ischaemia was simulated (except time controls) by superfusion of hypoxic Tyrode (N₂ 95% and CO₂ 5%) without glucose and increasing the stimulation frequency to 1 Hz. Forty minutes after ischaemic rigor development, trabeculae were reperfused for 60 min with oxygenated normal Tyrode and basal stimulation conditions (0.2 Hz). The recovery of F_dev (F_dev,rec) was expressed as a percentage of the F_dev,start. Trabeculae were preconditioned for 15 min with normal Tyrode saturated with 3.8 vol% sevoflurane 30 min before simulated ischaemia and reperfusion (SI/R). After washout of sevoflurane, trabeculae were superfused for 15 min with normal Tyrode until SI/R. In a separate experimental group, sevoflurane preconditioning was preceded by addition of Go6976 (GO) (50 nM; PKC- inhibitor; Biomol).

View larger version (20K): [in this window] [in a new window] [Download PowerPoint slide]   Fig 1 Overview of the randomized experimental design for trabeculae subjected to an I/R-protocol and contractile function measurements (A–E) or immunofluorescent analysis of PKC- translocation (F–I). SI/R, simulated ischaemia and reperfusion; SEVO, sevoflurane; MPG, n-(2-mercaptopropionyl)-glycine (300 µM); 5-HD, 5-hydroxydecanoic acid sodium (100 µM); ROT, rottlerin (1 µM).

 
Digital imaging fluorescence microscopy of PKC- distribution
The sevoflurane-induced subcellular redistribution of PKC- was studied by immunofluorescent staining followed by digital imaging fluorescence microscopy in trabeculae subjected to sevoflurane alone or in combination with GO (50 nM), n-(2-mercaptopropionyl)-glycine (MPG; 300 µM; ROS scavenger; Sigma-Aldrich), 5-hydroxydecanoic acid sodium (5-HD; 100 µM; mitoK⁺_ATP inhibitor; Sigma-Aldrich), or rottlerin (ROT; 1 µM; PKC- inhibitor, Sigma-Aldrich), as described earlier.^{14 17} Briefly, trabeculae subjected to an experimental protocol (Fig. 1, Groups F–I) were embedded in gelatin and cross-sections were subsequently fixed, stained for PKC- [rabbit anti-protein kinase C- (664–672) serum: aS-2416S (100% cross-reactivity with PKC- and 0% cross-reactivity with all other PKC isozymes); Research and Diagnostic Antibodies, North Las Vegas, NV, USA] and counterstained for nuclei [4',6-diamidino-2-phenylindole (DAPI); Vectashield, Vector Laboratories, Burlingame, CA, USA], and mitochondria (anti-GRP75; Stressgen, Ann Arbor, MI, USA), or the sarcolemma [wheat germ agglutinin (WGA); Molecular Probes, Leiden, The Netherlands]. The sections were analysed with a ZEISS Axiovert 200 Marianas^TM inverted digital imaging microscope using Slidebook^TM software (Slidebook^TM version 4.1; 3l, Denver, CO, USA).

Statistical analysis
All values are given as mean (SEM). Force experiments were analysed using analysis of variance followed by a Tukey post hoc test. A P-value of <0.05 was considered to reflect a significant difference.

	Results

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General characteristics
Table 1 shows the general characteristics of trabeculae subjected to SI/R (except time controls). In the experimental group SI/R+GO, the time to rigor was slightly prolonged when compared with the time to rigour of the SI/R group. However, there was no correlation between the time to rigour and final contractile recovery, and therefore this difference did not bias our observations.

View this table: [in this window] [in a new window]   Table 1 General characteristics of trabeculae subjected to ischaemia and reperfusion. CSA, cross-sectional area; Fdev,start, initial developed force before the experiment; Fpot,start, potentiated force development before the experiment; Fpas,start, passive force before the experiment; SI/R, simulated ischaemia and reperfusion; SEVO, sevoflurane; GO, Go6976. *P<0.05 vs SI/R and SI/R+SEVO+GO

 
Sevoflurane-induced cardioprotection depends on PKC-
At the end of the full experimental protocol (170 min), F_dev decreased to 79 (7)% [n=6; (time control)] whereas SI/R reduced the contractile recovery (F_dev,rec) to 47 (3)% [(SI/R); n=9; P<0.05 vs (time control)] (Fig. 2). Pre-treatment with sevoflurane improved the F_dev,rec to 65 (3)% [(SI/R+SEVO); n=8; P<0.05 vs (SI/R)]. In trabeculae with PKC- inhibition by GO, sevoflurane-induced cardioprotection was completely abolished [42 (4)% [(SI/R+SEVO+GO); n=10; P<0.05 vs (SI/R+SEVO)]. PKC- inhibition by GO before SI/R did not show intrinsic activity on F_dev,rec [40 (6)% (SI/R+GO); n=5, P>0.05 vs (SI/R)].

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig 2 The role of PKC- in sevoflurane-induced cardioprotection. Recovery of the developed force (Fdev,rec) is expressed as a fraction of the initial developed force (Fdev,start). Pretreatment with sevoflurane increased the post-ischaemic contractile force recovery and this protective effect was attenuated in trabeculae treated with Go6976 (50 nM). SI/R, simulated ischaemia and reperfusion; SEVO, sevoflurane; GO, Go6976. Data are mean (SEM); time control, n=6; SI/R, n=9; SI/R+SEVO, n=8; SI/R+SEVO+GO, n=10; SI/R+GO, n=5.

 
PKC- translocation in response to sevoflurane
In order to elucidate further the role of PKC- activation in sevoflurane-induced cardioprotection, the subcellular distribution of PKC- was evaluated in direct response to sevoflurane. Figure 3A shows the translocation pattern of PKC- in response to sevoflurane and sevoflurane in combination with GO in cross-sections of isolated trabeculae. In Figure 3A, green represents the specific PKC- staining, blue the nuclear DAPI staining, and red the WGA staining of the sarcolemma. In control trabeculae (Fig. 3A, Control), PKC- is distributed homogeneously in the cytosol. In response to sevoflurane, PKC- predominantly translocated into distinct particles (Fig. 3A, SEVO, white arrows), which co-localized with mitochondrial heat shock protein GRP75 (Fig. 3B, white arrows point to corresponding particles). Correlation factors between the green channel (PKC-) and red channel (GRP75 in mitochondrial matrix) were calculated to quantify sevoflurane-induced PKC- translocation into the mitochondria. The correlation factor, as determined by the imaging software, in controls was 0.22 and increased by sevoflurane treatment to 0.59 (maximal correlation factor is 1). In addition, occasional larger patches (interstitial cells) and more linear, membrane-like staining of PKC- (sarcolemmal or subsarcolemmal structures) were also seen. Most importantly, PKC- translocation was not detected in trabeculae treated with GO (Fig. 3A, SEVO+GO; the correlation factor between PKC- and GRP75 in mitochondria decreased to 0.32) and GO treatment itself did not affect PKC- translocation (not shown). To identify whether PKC- translocation occurs upstream or downstream of ROS-production, opening of mitoK⁺_ATP channels, or PKC- activation, PKC- translocation was studied in trabeculae treated with MPG, 5-HD, or ROT, respectively (Fig. 4). In trabeculae exposed to MPG, the sevoflurane-induced translocation of PKC- was abolished (Fig. 4, SEVO+MPG). Interestingly, sevoflurane-induced PKC- translocation was not abolished by 5-HD (Fig. 4, SEVO+5HD) or ROT (Fig. 4, SEVO+ROT). These data suggest that sevoflurane activates PKC- via ROS-production, but opening of mitoK⁺_ATP channels and activation of PKC- are not involved or act downstream of PKC- activation.

View larger version (123K): [in this window] [in a new window] [Download PowerPoint slide]   Fig 3 PKC- translocation in response to sevoflurane in cross-sections of isolated rat trabeculae. (A) In all panels, green represents specific PKC- staining, blue represents DAPI staining of the nuclei and red represents WGA staining of the sarcolemma. In control trabeculae, PKC- is predominantly located in the cytosol. After sevoflurane exposure, PKC- is detected in circumscript dots located within the cytosol (SEVO, white arrows). This sevoflurane-induced PKC- translocation is effectively attenuated by Go6976 (50 nM) (SEVO+GO). Go6976 itself had no intrinsic effect on PKC- translocation. (B) PKC- colocalizes with the mitochondria after sevoflurane-induced preconditioning. In these panels, green represents specific PKC- staining, blue the DAPI staining of the nuclei, and red the specific antibody against mitochondrial heat-shock protein GRP75. After sevoflurane preconditioning, PKC- (PKC- panel, white arrows) translocates towards mitochondria (GRP75 panel, white arrows) indicated by yellow in co-localization analyses (PKC-+GRP75 panel, white arrows). SEVO, sevoflurane; GO, Go6976.

 

View larger version (82K): [in this window] [in a new window] [Download PowerPoint slide]   Fig 4 Sevoflurane-induced PKC- tranlocation in relation to common mediators of cardioprotective signal transduction pathways. In all panels, green represents specific PKC- staining, blue the DAPI staining of the nuclei, and red the WGA staining of the sarcolemma. Sevoflurane-induced a translocation of PKC- from the cytosol towards the mitochondria (Fig. 3). This translocation was reduced by scavenging ROS during preconditioning with MPG (300 µM) (SEVO+MPG panel). Interestingly, sevoflurane-induced PKC- translocation was not attenuated by 5HD (100 µM) (SEVO+5HD panel) or by ROT (1 µM) (SEVO+ROT panel).

 

	Discussion

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The present study shows for the first time that, in addition to the previously described role of the Ca²⁺-independent PKC- isoform, sevoflurane-induced cardioprotection also involves activation of the Ca²⁺-dependent isoform PKC-. In addition, sevoflurane-induced translocation of PKC- is dependent on the production of ROS, occurs upstream of opening of mitoK⁺_ATP channels, and is independent of PKC- activation.

Cardioprotective signalling elicited by pre-conditioning has been demonstrated to rely on PKC activation. However, the sequences of events and the specific PKC isoforms involved in this protective cascade have been widely discussed.^{2 4 18} PKC- and - have been considered most important in ischaemic,¹⁹ opioid,²⁰ and volatile anaesthetic-induced preconditioning.^{6 7} Indeed, we previously demonstrated that sevoflurane-induced cardioprotective responses in our model depend on PKC- activation, whereas PKC- is not primarily involved. Furthermore, we showed that PKC- translocation in response to sevoflurane depends on ROS production, but not opening of mitoK⁺_ATP channels.¹⁴ Importantly, the present data show for the first time that the Ca²⁺-dependent PKC- isoform is activated by sevoflurane and is also involved in sevoflurane-induced cardioprotective signalling. It has previously been shown that volatile anaesthetics are able to increase PKC- activity in purified rat brain extracts and skeletal muscle.²¹ In addition, PKC- is activated, in response to other preconditioning stimuli, such as ischaemia,^{11 22} phenylepinephrine,²³ Ca²⁺,⁹ and opioids,²⁰ and specific PKC- inhibition has been reported to abolish cardioprotection induced by ischaemic preconditioning (IPC).^{24 25}

Our data suggest that PKC- is activated by sevoflurane via the formation of ROS, but not opening of mitoK⁺_ATP channels. This ROS-dependent activation of PKC- has been supported by Hoek and colleagues²⁵ demonstrating that PKC- inhibition attenuated cardioprotection by IPC, but did not affect ROS-production during pre-conditioning. However, in contrast to our findings Hassouna and colleagues²⁴ showed that IPC and diazoxide-induced pre-conditioning involved PKC- acting downstream of the mitoK⁺_ATP channels. In addition, it is reported that upon pre-conditioning with the mitoK⁺_ATP channel opener diazoxide, PKC- translocated towards the sarcolemma.²⁶ Diazoxide and sevoflurane increase intracellular ROS production, and scavenging ROS with MPG attenuates subsequent pre-conditioning.^{14 27} However, sevoflurane-induced ROS production has been reported to be independent of mitoK⁺_ATP channels,²⁸ and therefore, the explanation underlying these contradictory findings may relate to differences in the mechanism of ROS production.

How sevoflurane-induced PKC activation contributes to the improved contractile recovery after I/R injury remains speculative. PKC- has been demonstrated to be actively involved in the regulation of cell survival and apoptosis,^{29 30} in addition to direct involvement in the regulation of cardiomyocyte contractility.^31–34 Although others showed that PKC- translocates towards the sarcolemma in response to Ca²⁺ and ischaemia,⁹ we found that PKC- translocated towards mitochondria. This implies that direct modification of contractile or Ca²⁺-handling proteins in our model may be less likely. Interestingly, mitochondrial PKC- has been associated with increased phosphorylation of the anti-apoptotic protein Bcl2.³⁵ Recently, Imahashi and colleagues³⁶ showed that modulation of myocardial energy metabolism by Bcl2 over expression contributed to increased recovery after I/R. We therefore speculate that this may be among the potential mitochondrial targets of PKC-. As we previously demonstrated,¹⁴ PKC- translocated to the sarcolemma in response to sevoflurane preconditioning, but the exact target remains speculative. Target proteins may include Ca²⁺-handling proteins, which could contribute to a reduction in Ca²⁺ overload during I/R. We recently demonstrated that PKC- translocation in response to sevoflurane was dependent on the reverse mode of the Na⁺/Ca²⁺-exchanger illustrating the intimate relationship between Ca²⁺-handling and cardioprotective signalling.³⁷ However, other potential targets in the sarcolemma have been suggested, including PKC--dependent sensitization of the sarcolemmal ATP-sensitive potassium channel.³⁸ Future studies in our laboratory will be aimed to examine the relative role of the different PKC-isoforms involved in volatile anaesthetic-induced cardioprotection.

Serial signalling steps between different PKC-isoforms have been reported to occur in several cardioprotective signalling cascades. Recently, Inagaki and Mochly-Rosen³⁹ showed that ethanol-induced cardioprotection relies on both PKC- and PKC- activation. In addition, serial PKC signalling was also suggested in human atrial appendages with respect to PKC- and PKC-.²⁴ In contrast, the present study shows that PKC- activation is independent of PKC-, although others showed that PKC- increases PKC- protein levels via stabilization of PKC- mRNA.⁴⁰ Therefore, serial PKC signalling with respect to PKC- and PKC- seems to be less likely in our model, because of the acute and parallel activation of different isoforms by sevoflurane.

Finally, the finding that the Ca²⁺-dependent PKC- isoform contributes to sevoflurane-induced protective signalling may be relevant for the clinical induction of cardioprotection in the pathological myocardium. Alterations in myocardial Ca²⁺-handling and expression of PKC-isoforms have been demonstrated in diseased myocardium, that is, because of heart failure. PKC- activity is dose-dependently modified by Ca²⁺,⁴¹ and likewise its activity and expression are increased in failing myocardium.⁴² This may contribute to alterations in sevoflurane-induced cardioprotective signalling in diseased hearts.

Study limitations
This study largely depends on the specificity of the indolocarbazole compound GO. GO has been described to discriminate effectively between Ca²⁺-dependent PKC isoforms with no effect on the novel PKC isoforms.⁴³ In the present study, we focused on PKC-, as representative of the Ca²⁺-dependent PKC isoforms, in the signalling cascade of sevoflurane-induced protective signalling. The specificity of GO was confirmed as PKC- translocation induced by sevoflurane was abolished by this inhibitor. However, with this approach, we cannot entirely exclude the involvement of the other Ca²⁺-dependent isoform PKC-ß.

In summary, in addition to the previously described role of the Ca²⁺-independent PKC- isoform, sevoflurane-induced preconditioning also depends on activation of the Ca²⁺-dependent PKC- isoform. During sevoflurane-induced preconditioning, PKC- translocates towards the mitochondria. This mitochondrial translocation of PKC- is dependent on the production of ROS, but is independent of opening of mitoK⁺_ATP channels and PKC-. Although the exact relationship between PKC- and PKC- remains to be established, the co-involvement of the Ca²⁺-dependent PKC- isoform in sevoflurane-induced cardioprotection may be of clinical relevance for the development of cardioprotective strategies in the diseased myocardium with altered Ca²⁺ handling.

	Acknowledgements

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The Institute for Cardiovascular Research Vrije Universiteit (ICaR-VU, Amsterdam, The Netherlands) provided support for this study.

R.A.B. is an MD-clinical research trainee supported by ZonMw, The Netherlands Organization for Scientific Research, The Hague, The Netherlands.

	References

Top Abstract Introduction Methods Results Discussion Acknowledgements References

 
1 Weber NC, Schlack W. The concept of anaesthetic-induced cardioprotection: mechanisms of action. Best Pract Res Clin Anaesthesiol (2005) 19:429–43.[CrossRef][Medline]

2 De Hert SG, Turani F, Mathur S, Stowe DF. Cardioprotection with volatile anesthetics: mechanisms and clinical implications. Anesth Analg (2005) 100:1584–93.[Abstract/Free Full Text]

3 Riess ML, Stowe DF, Warltier DC. Cardiac pharmacological preconditioning with volatile anesthetics: from bench to bedside? Am J Physiol Heart Circ Physiol (2004) 286:H1603–7.[Abstract/Free Full Text]

4 Zaugg M, Lucchinetti E, Uecker M, Pasch T, Schaub MC. Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms. Br J Anaesth (2003) 91:551–65.[Abstract/Free Full Text]

5 Naruse K, King GL. Protein kinase C and myocardial biology and function. Circ Res (2000) 86:1104–6.[Free Full Text]

6 Novalija E, Kevin LG, Camara AK, et al. Reactive oxygen species precede the epsilon isoform of protein kinase C in the anesthetic preconditioning signaling cascade. Anesthesiology (2003) 99:421–8.[CrossRef][Web of Science][Medline]

7 Obal D, Weber NC, Zacharowski K, et al. Role of protein kinase C-epsilon (PKCepsilon) in isoflurane-induced cardioprotection. Br J Anaesth (2005) 94:166–73.[Abstract/Free Full Text]

8 Przyklenk K, Hata K, Kloner RA. Is calcium a mediator of infarct size reduction with preconditioning in canine myocardium? Circulation (1997) 96:1305–12.[Abstract/Free Full Text]

9 Miyawaki H, Ashraf M. Ca²⁺ as a mediator of ischemic preconditioning. Circ Res (1997) 80:790–9.[Abstract/Free Full Text]

10 Dekker LRC, Coronel R, VanBavel E, Spaan JAE, Opthof T. Intracellular Ca²⁺ delay of ischemia-induced electrical uncoupling in preconditioned rabbit ventricular myocardium. Cardiovasc Res (1999) 44:101–12.[Abstract/Free Full Text]

11 Strasser RH, Simonis G, Schon SP, et al. Two distinct mechanisms mediate a differential regulation of protein kinase C isozymes in acute and prolonged myocardial ischemia. Circ Res (1999) 85:77–87.[Abstract/Free Full Text]

12 Miyawaki H, Zhou X, Ashraf M. Calcium preconditioning elicits strong protection against ischemic injury via protein kinase C signaling pathway. Circ Res (1996) 79:137–46.[Abstract/Free Full Text]

13 Hanley PJ, ter Keurs HE, Cannell MB. Excitation–contraction coupling in the heart and the negative inotropic action of volatile anesthetics. Anesthesiology (2004) 101:999–1014.[CrossRef][Web of Science][Medline]

14 Bouwman RA, Musters RJ, Beek-Harmsen BJ, De Lange JJ, Boer C. Reactive oxygen species precede protein kinase C-delta activation independent of adenosine triphosphate-sensitive mitochondrial channel opening in sevoflurane-induced cardioprotection. Anesthesiology (2004) 100:506–14.[CrossRef][Web of Science][Medline]

15 de Ruijter W, Musters RJP, Boer C, et al. The cardioprotective effect of sevoflurane depends on protein kinase C activation, opening of mitochondrial K+ATP channels, and the production of reactive oxygen species. Anesth Analg (2003) 97:1370–6.[Abstract/Free Full Text]

16 Schouten VJ, van Deen JK, de Tombe P, Verveen AA. Force–interval relationship in heart muscle of mammals. A calcium compartment model. Biophys J (1987) 51:13–26.[Web of Science][Medline]

17 Bouwman RA, van't Hof FN, De Ruijter W, et al. The mechanism of sevoflurane-induced cardioprotection is independent of the applied ischaemic stimulus in rat trabeculae. Br J Anaesth (2006) 97:307–14.[Abstract/Free Full Text]

18 Mackay K, Mochly-Rosen D. Localization, anchoring, and functions of protein kinase C isozymes in the heart. J Mol Cell Cardiol (2001) 33:1301–7.[CrossRef][Web of Science][Medline]

19 Baines CP, Zhang J, Wang GW, et al. Mitochondrial PKCepsilon and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCepsilon-MAPK interactions and differential MAPK activation in PKCepsilon-induced cardioprotection. Circ Res (2002) 90:390–7.[Abstract/Free Full Text]

20 Fryer RM, Wang Y, Hsu AK, Gross GJ. Essential activation of PKC-delta in opioid-initiated cardioprotection. Am J Physiol Heart Circ Physiol (2001) 280:H1346–53.[Abstract/Free Full Text]

21 Adamo AI. Effect of halothane on conventional protein kinase C translocation and down-regulation in rat cerebrocortical synaptosomes. Br J Anaesth (1997) 78:189–96.[Abstract/Free Full Text]

22 Kitakaze M, Funaya H, Minamino T, et al. Role of protein kinase C-alpha in activation of ecto-5'-nucleotidase in the preconditioned canine myocardium. Biochem Biophys Res Commun (1997) 239:171–5.[CrossRef][Web of Science][Medline]

23 Rehring TF, Friese RS, Cleveland JC, et al. Alpha-adrenergic preservation of myocardial pH during ischemia is PKC isoform dependent. J Surg Res (1996) 63:324–7.[CrossRef][Web of Science][Medline]

24 Hassouna A, Matata BM, Galinanes M. PKC-epsilon is upstream and PKC-alpha is downstream of mitoKATP channels in the signal transduction pathway of ischemic preconditioning of human myocardium. Am J Physiol Cell Physiol (2004) 287:C1418–25.[Abstract/Free Full Text]

25 Hoek TLV, Becker LB, Shao ZH, Li CQ, Schumacker PT. Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circ Res (2000) 86:541–8.[Abstract/Free Full Text]

26 Wang Y, Ashraf M. Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca²⁺ overload injury in rat myocardium. Circ Res (1999) 84:1156–65.[Abstract/Free Full Text]

27 Forbes RA, Steenbergen C, Murphy E. Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. Circ Res (2001) 88:802–9.[Abstract/Free Full Text]

28 Kevin LG, Novalija E, Riess ML, et al. Sevoflurane exposure generates superoxide but leads to decreased superoxide during ischemia and reperfusion in isolated hearts. Anesth Analg (2003) 96:949–55.[Abstract/Free Full Text]

29 Nakashima S. Protein kinase C alpha (PKC alpha): regulation and biological function. J Biochem (Tokyo) (2002) 132:669–75.[Abstract/Free Full Text]

30 Michie AM, Nakagawa R. The link between PKCalpha regulation and cellular transformation. Immunol Lett (2005) 96:155–62.[CrossRef][Web of Science][Medline]

31 Braz JC, Gregory K, Pathak A, et al. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med (2004) 10:248–54.[CrossRef][Web of Science][Medline]

32 Allen BG, Katz S. Phosphorylation of cardiac junctional and free sarcoplasmic reticulum by PKC alpha, PKC beta, PKA and the Ca²⁺/calmodulin-dependent protein kinase. Mol Cell Biochem (1996) 155:91–103.[Web of Science][Medline]

33 Hahn HS, Marreez Y, Odley A, et al. Protein kinase Calpha negatively regulates systolic and diastolic function in pathological hypertrophy. Circ Res (2003) 93:1111–9.[Abstract/Free Full Text]

34 Meldrum DR, Cleveland JC Jr, Rowland RT, Banerjee A, Harken AH. Calcium-induced inotropy is in part mediated by protein kinase C. J Surg Res (1996) 63:400–5.[CrossRef][Web of Science][Medline]

35 Ruvolo PP, Deng X, Carr BK, May WS. A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem (1998) 273:25436–42.[Abstract/Free Full Text]

36 Imahashi K, Schneider MD, Steenbergen C, Murphy E. Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res (2004) 95:734–41.[Abstract/Free Full Text]

37 Bouwman RA, Salic K, Padding FG, et al. Cardioprotection via activation of protein kinase C-delta depends on modulation of the reverse mode of the Na+/Ca²⁺ exchanger. Circulation (2006) 114:I226–32.[CrossRef][Web of Science][Medline]

38 Marinovic J, Bosnjak ZJ, Stadnicka A. Preconditioning by isoflurane induces lasting sensitization of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel by a protein kinase C-delta-mediated mechanism. Anesthesiology (2005) 103:540–7.[CrossRef][Web of Science][Medline]

39 Inagaki K, Mochly-Rosen D. DeltaPKC-mediated activation of epsilonPKC in ethanol-induced cardiac protection from ischemia. J Mol Cell Cardiol (2005) 39:203–11.[CrossRef][Web of Science][Medline]

40 Romanova LY, Alexandrov IA, Nordan RP, Blagosklonny MV, Mushinski JF. Cross-talk between protein kinase C-alpha (PKC-alpha) and -delta (PKC-delta): PKC-alpha elevates the PKC-delta protein level, altering its mRNA transcription and degradation. Biochemistry (1998) 37:5558–65.[CrossRef][Medline]

41 Slater SJ, Stagliano BA, Seiz JL, et al. Effects of ethanol on protein kinase C activity induced by filamentous actin. Biochim Biophys Acta (2001) 1544:207–16.[CrossRef][Medline]

42 Bowling N, Walsh RA, Song G, et al. Increased protein kinase C activity and expression of Ca²⁺-sensitive isoforms in the failing human heart. Circulation (1999) 99:384–91.[Abstract/Free Full Text]

43 Martiny-Baron G, Kazanietz MG, Mischak H, et al. Selective inhibition of protein kinase C isozymes by the indolocarbazole Go 6976. J Biol Chem (1993) 268:9194–7.[Abstract/Free Full Text]

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