AJP - Heart Track the topics, authors and articles important to you
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 279: H2269-H2276, 2000;
0363-6135/00 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (12)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Okubo, S.
Right arrow Articles by Kukreja, R. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Okubo, S.
Right arrow Articles by Kukreja, R. C.
Vol. 279, Issue 5, H2269-H2276, November 2000

Tyrosine kinase signaling in action potential shortening and expression of HSP72 in late preconditioning

Shinji Okubo1, Nelson L. Bernardo2, Gary T. Elliott3, Michael L. Hess2, and Rakesh C. Kukreja2

2 Division of Cardiology, Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298; 1 Department of Cardiology, Kanazawa Medical University, Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan; and 3 Corixa Corporation, Hamilton, Montana 59840


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We investigated the role of tyrosine kinase (TK) signaling in the opening of the ATP-sensitive K+ (KATP) channel and 72-kDa heat shock protein (HSP72) expression during late preconditioning. Rabbits were subjected to surgical operation (sham) or were preconditioned (PC) with four cycles of 5 min of ischemia and 10 min of reperfusion. Twenty-four hours later, animals were subjected to 30 min of ischemia and 180 min of reperfusion. Genistein (1 mg/kg ip) was used to block the receptor TK. Six groups were studied: control, sham, genistein-sham, PC, genistein-PC, and vehicle-PC group (1% dimethyl sulfoxide). Genistein or vehicle was given 30 min before the surgical procedure. Genistein pretreatment decreased the expression of HSP72 in PC hearts and suppressed action potential duration shortening during ischemia in sham and PC groups. Infarct size (%risk area) was reduced in the PC (11.6 ± 1.0%) and vehicle-PC (19.3 ± 2.0%) compared with the control (40.0 ± 3.8%) or sham (46.0 ± 2.0%) groups (P < 0.05). Genistein pretreatment increased infarct size to 46.4 ± 4.1% in the PC hearts. We conclude that TK signaling is involved in KATP channel opening and HSP72 expression during late PC.

genistein; adenosine 5'-triphosphate-sensitive potassium channel; ischemia-reperfusion; 72-kDa heat shock protein


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

ISCHEMIC PRECONDITIONING (PC) is a phenomenon whereby exposure of the myocardium to a brief episode of ischemia and reperfusion reduces tissue necrosis during a subsequent sustained ischemia (36). PC has also been shown to induce delayed phase of protection that appears 24 h later, a phenomenon termed as the "second window of protection" or late PC (25, 29). The mechanism(s) of late PC is not clearly understood, although a number of receptors (41) and intracellular signaling pathways such as protein kinase C (PKC) (4, 24, 51) and tyrosine phosphorylation (19, 40) have been identified as being the essential components of the cardioprotective effect.

Recent evidence suggests that opening of the ATP-sensitive K+ (KATP) channel mediates the late phase of ischemic protection induced by PC (7), heat stress (18, 43), and pharmacological agents such as adenosine agonist (5, 8), opioids (14), and monophosphoryl lipid A (13, 20, 33). In addition, late PC is also accompanied by increased expression of the 72-kDa heat shock protein (HSP72) (29). Several studies suggest that overexpression of HSP72 induces a cardioprotective effect (30), although its direct cause-and-effect relationship in the development of late PC remains uncertain (45). Because increased expression of HSP72 and activation of KATP channel appear to be the downstream final events in late PC, we hypothesized that a common signaling pathway may mediate these effects. Accordingly, the goals of the present study were 1) to demonstrate whether the activation of tyrosine kinase (TK) signaling with PC is related with the opening of the KATP channel (the shortening of action potential duration; APD) and expression of HSP72 in the heart and 2) to show whether the cardioprotective effect of late PC is abrogated by genistein, the inhibitor of receptor TK. Using our in situ rabbit model of myocardial infarction, we demonstrated that genistein blocked APD shortening during sustained ischemia, diminished the expression of HSP72, and blocked the delayed cardioprotective effect of PC.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals. Male New Zealand White rabbits (2.8-3.3 kg) were used for the studies. The rabbits were supplied by the Prince Rabbitry (Oakhill, WV) or the Blue and Gray Rabbitry (Unionville Lane, VA). The animals were allowed to readjust to the new housing environment for at least a week before the experiment. Animals were cared for and used in accordance with the guidelines of the Committee on Animals of Virginia Commonwealth University.

Experimental protocol. The rabbits were randomly assigned into one of the following six groups (Fig. 1). Group I (control) underwent 30 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion (I/R). Group II are sham-operated animals. Because the surgical intervention itself can potentially induce modified infarct size, sham-operated animals were also used as controls. The chest was opened for the duration of PC protocol on day 1 and then closed. Twenty-four hours later, the chest was reopened and the animals were subjected to I/R protocol as in group I. Group III are sham rabbits (as in group II) that received genistein (Ge, 1 mg/kg ip; Research Biochemicals) 30 min before the surgery on day 1. Twenty-four hours later, the animals underwent I/R protocol as in group I. In group IV (PC), PC rabbits underwent a sequence of four cycles of 5 min of LAD occlusion and 10 min of reperfusion 24 h before the I/R protocol as in group I. Group V (Ge-PC) rabbits underwent the same protocol as in group IV except that the animals were injected with genistein 30 min before PC. Group VI (Veh-PC) rabbits received vehicle (Veh; 1% DMSO in saline) 30 min before PC. For measurement of HSP72, three hearts from each of the sham, Ge-PC, and PC groups were collected on day 2 just before initiation of prolonged I/R protocol. For positive control, three additional animals were subjected to whole body hyperthermia by raising of the temperature to 42°C for 15 min 24 h before death, as described previously (19).


View larger version (22K):
[in this window]
[in a new window]
  		Fig. 1.   Experimental design. Preconditioned (PC) hearts underwent 4 cycles of 5 min of left coronary artery occlusions, each separated by 10 min of reperfusion. All animals were subjected to 30 min of regional ischemia followed by 3 h of reperfusion. See METHODS for experimental group descriptions. Ope, operation; Occl, occlusion; Rep, reperfusion; Ge, genistein; Veh, vehicle.

Surgical preparation. The animals were anesthetized with an intramuscular injection of ketamine-HCl (35 mg/kg) and xylazine (5 mg/kg). Further injections of ketamine-xylazine were given as needed throughout the surgical procedure. All surgical procedures were performed under sterile conditions. Arterial blood gases and pH were measured during the experimental protocol to ensure proper physiological respiration during the experiment. The chest was opened by a left thoracotomy in the fourth intercostal space, and the pericardium was opened to expose the heart. A 5-0 silk suture with an atraumatic needle was then passed around the LAD. The snare was pulled and then fixed in place with a hemostat, thus inducing regional ischemia. Myocardial ischemia was confirmed visually in situ by regional cyanosis, S-T segment elevation/depression or T wave inversion, hypokinetic movement of the myocardium, and relative hypotension. The details of the surgical procedures have been reported previously (7).

Measurement of infarct size. Risk area was demarcated by Evans blue, and infarct size was measured with the use of tetrazolium-stained sections (7). The area for each region was determined by digital planimetry with computer morphometry by use of Bioquant imaging software. Infarct size was expressed both as a percentage of the total left ventricle (LV) and as a percentage of the ischemic risk area.

Measurement of hemodynamics. Hemodynamic parameters such as systolic, diastolic, and mean arterial pressures and rate-pressure product (the product of the heart rate and peak arterial pressure) were continuously measured throughout the duration of the experimental protocol by use of a strip-chart recorder.

Epicardial APD. The activity of the ventricular KATP channel during ischemia was assessed with a hand-held placement electrode (MAP electrode; EP Technologies, Sunnyvale, CA) and recorded at a chart speed of 100 mm/s (7, 8). The electrode was placed with a constant pressure to the perceived center of the ischemic zone. Signals were amplified with direct-current-coupled differential amplifies at a frequency range of 0.04-500 Hz. The APD at 50 and 90% repolarization (APD50 and APD90, respectively) was determined during preischemia and after every 10 min of LAD occlusion. The APD was accepted only if it fulfilled the following criteria: 1) constant configuration and stable resting membrane potential and 2) stable amplitude of phase 2 > 10 mV during control recording.

Measurement of HSP72. The expression of HSP72 in the LV was measured by Western blotting as described previously (18) with the use of a mouse monoclonal antibody cross-reacting to the 70-kDa HSP (HSP70; Stressgen Biotechnologies-Canada). The second antibody was horseradish peroxide-conjugated rabbit anti-mouse IgG.

Statistics. All measurements of infarct size, risk areas, and APDs are expressed as group means ± SE. Changes in hemodynamics, APD, and infarct size variables were analyzed by a one-way repeated-measure ANOVA to determine the effect of time, group, and time-by-group interaction. If the global tests showed major interactions, post hoc contrasts between different time points within the same group or between different groups were performed by use of a t-test. Statistical differences with P value < 0.05 were considered significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

A total of 75 rabbits were used in this study. A summary of the number of animals in each group and the reasons for exclusion is described in Table 1.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Exclusion data

APD. Figure 2 shows changes in APD50 (Fig. 2A) and APD90 (Fig. 2B) during ischemia in the six experimental groups. There was significant shortening of APD50 (expressed as %preischemic baseline) after 10, 20, and 30 min of ischemia in the control, sham, PC, and Veh-PC groups. Experimental groups treated with genistein, i.e., PC (Ge-PC) or sham (Ge-sham) groups, demonstrated significant suppression of APD50 shortening compared with the untreated groups, i.e., control, sham, and PC groups (Fig. 2A). No significant difference in the APD shortening was observed among the control, sham, PC, and Veh-PC groups. Baseline APD values were also not significantly different among the six groups (not shown). A similar trend in the mean percent changes in APD90 was observed (Fig. 2B).


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 2.   Monophasic action potential duration (APD) at 50% repolarization (APD50; A) and 90% repolarization (APD90; B) measured as percentage of baseline from 10 to 30 min after ischemia. All values are expressed as means ± SE. A: aP < 0.05 vs. control; bP < 0.05 vs. sham; cP < 0.05 vs. PC and Veh-PC. B: aP < 0.05 vs. sham; bP < 0.05 vs. PC and Veh-PC.

Expression of HSP72. An increase in the synthesis of HSP72 was observed 24 h after PC compared with sham animals subjected only to the surgery protocol. Genistein-pretreated rabbits demonstrated decreased expression of HSP72 (Fig. 3). Positive controls from the myocardial samples derived from heat-shocked rabbits also showed enhanced expression of HSP72 similar to the PC hearts.


View larger version (37K):
[in this window]
[in a new window]
  		Fig. 3.   Western blot showing 72-kDa heat shock protein (HSP72) in sham, PC, and genistein-treated PC hearts (Ge-PC). Note that myocardial samples from rabbits subjected to heat stress at 42°C were used as a positive control, and standard HSP72 was used as a marker.

Infarct size. No significant difference in the risk areas was observed between the experimental groups (Fig. 4A). PC resulted in a marked decrease in the infarct size (expressed as %risk area) from 40.0 ± 3.8 in the sham group to 11.6 ± 1.0% in the PC group, a 71% reduction (mean ± SE, P < 0.05; Fig. 4C). The infarct size increased significantly to 46.4 ± 4.1% in the Ge-PC rabbits (P < 0.05). Infarct size in Veh-PC rabbits was 19.3 ± 2.2%, which was not significantly different compared with the nontreated PC hearts, i.e., 11.6 ± 1.0% (P > 0.05). Furthermore, Ge-sham animals had an infarct size of 41.7 ± 2.3%, which was not different compared with the control (40 ± 3.8%) or sham (46.0 ± 2.0%). A similar trend in the changes in infarct size was observed when expressed as percentage of LV (Fig. 4B).


View larger version (31K):
[in this window]
[in a new window]
  		Fig. 4.   Bar diagram showing risk areas [expressed as %left ventricle (LV); A], infarct size (expressed as %LV; B), and risk area (C). See METHODS for experimental group descriptions.

Hemodynamics. Heart rate, mean arterial blood pressure, and rate-pressure product are shown in Table 2. Except for the indicated differences, these parameters were comparable among the six groups at baseline and during occlusion and the reperfusion period. All groups had a similar decline in blood pressure after coronary occlusion, with no tendency toward recovery during the reperfusion period.

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Hemodynamics data


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Recent studies have shown that the opening of the KATP channel plays an important role in late PC induced by sublethal ischemia (7), heat stress (18, 43), pharmacological agents such as adenosine agonist, 2-chloro-N6-cyclo-pentyladenosine (8), opioids (5, 14), and monophosphoryl lipid A (20). The activation of this channel is at least partially responsible for the increase in outward K+ currents, shortening of APD, and increase of extracellular K+ concentration during an anoxic or globally ischemic condition (6). Our results show that ischemia-induced shortening of epicardial APD (the indicator of surface KATP channel opening) was significantly blocked in the animals pretreated with genistein. Furthermore, this drug blocked PC-induced reduction in infarct size without exerting significant effect on infarct size in the control or sham animals. The enhanced expression of HSP72 after 24 h of PC was diminished in the animals pretreated with genistein. No major difference in the heart rate, mean arterial pressure, and rate-pressure product was observed among the six groups during the infarction protocol, suggesting that the changes in myocardial infarcts were independent of the systemic hemodynamics. Taken together, our data suggest that the TK signaling pathway regulates the opening of the KATP channel and synthesis of HSP72 during late PC in the rabbit heart.

TK signaling has been suggested to be an important mediator of acute and late PC (12, 19, 32). Utilizing genistein, the blocker of receptor TK, Maulik et al. (31) first demonstrated the importance of a TK-phospholipase D signaling pathway in classical PC of the isolated rat heart. Recently, Dawn et al. (12) suggested that TK signaling plays a dual role in the pathophysiology of late PC against myocardial stunning, i.e., it was essential not only for the initiation of this phenomenon on day 1 but also for the manifestation of cardioprotection on day 2. The mechanism(s) by which TK signaling may have influenced the development of late PC is not well understood. Our results show that genistein suppressed the APD shortening during ischemia, suggesting that inhibition of tyrosine phosphorylation interfered with the opening of the KATP channel.

Protein phosphorylation on serine and threonine residues modulates the activity of a variety of ion channels and consequently alters the excitability of many central neurons (21, 26). Protein phosphorylation at tyrosine residues has been found to acutely modulate neurotransmitter receptors (50) and ion channels (49), including Na+ channels (42), Ca2+ channels (1), and cyclic nucleotide-gated (34) and voltage gated cationic channels (52) as well as K+ channels. Genistein is an inhibitor for TK but scarcely inhibits the activity of serine and threonine kinases and other ATP analog-related enzymes. Recently, Okajima et al. (39) reported that genistein had a competitive antagonistic activity for A1 adenosine receptors in thyroid cells. However, it is unlikely that genistein blocked late PC by A1 adenosine receptors or with another pathway. Recently, Fryer et al. (15) suggested that the anticardioprotective effects of genistein in the in vivo rat model of PC were due to the inhibition of TK rather than inhibition of voltage-gated Na+ channels, A1 adenoside receptors, or PKC.

It has recently been shown that p38 mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase (MAPKAPK)-2 are strongly activated by ischemia in the perfused rat heart (10, 32). PC also induces a PKC-mediated rapid activation of p44/p42 MAPK in the cytosol that subsequently translocates to the nucleus, suggesting that MAPKs may play a role in myocardial adaptation to ischemic stress (44). Anisomycin, which activates MAPK kinases and hence the p38 MAPK and c-Jun NH2-terminal kinase (JNK) pathways, mimics PC in isolated rabbit hearts and myocytes (2, 3). This protection was blocked by 5-hydroxydecanote (5-HD), suggesting that the downstream effector of MAPK signaling is the opening of the mitochondrial KATP channel. Our data suggest a direct link between the activation of TK signaling by PC, leading to the shortening of APD. Recent studies suggest that cardioprotection due to opening of the KATP channel is independent of APD shortening. There was a lack of correlation between the APD shortening and cardioprotection with bimakalim and cromakalim, the openers of the KATP channel (17, 53). Garlid et al. (16) proposed that mitochondrial KATP channels could be involved in the cardioprotective effect of PC. With the use of the mitochondrial KATP channel opener diazoxide, a significant cardioprotective effect of the drug was demonstrated in the isolated perfused heart (16). Similar protective effects of diazoxide have been shown in ventricular myocytes (28, 48) and in vivo (38, 51). The cardioprotective effect of diazoxide was blocked by selective blockade of the mitochondrial KATP channel by 5-HD.

The mechanism by which TK signaling triggers the opening of the KATP channel is not clear, although several possibilities exist. For example, Maulik et al. (31) suggested that ischemic PC caused an activation of nuclear factor (NF)-kappa B that was dependent on p38 MAPK signaling. This may result in the stimulation of NF-kappa B-specific DNA protein binding, initiating the expression of inducible nitric oxide synthase (11) and, finally, the release of nitric oxide and potentially the opening of the KATP channel (47).

In the present investigation, we also observed reduced expression of HSP72 after 24 h of PC in the genistein-treated rabbits. The synthesis of HSPs involves activation of heat shock transcription factor (HSF)-1 after treatment of mammalian cells with stresses such as heat shock, heavy metals, or ethanol (27, 35). It has been shown that HSF-1 can be phosphorylated by the MAPK extracellular signal-regulated kinase (ERK)1. Also, HSF-1 can be phosphorylated in a ras-dependent manner by other members of the MAPK family such as JNKs and p38 protein kinases and possibly others (23). It is well known that substrates for MAPKs/JNKs include the transcription factors c-Jun, activating transcription factor (ATF)-2, and Elk-1. Phosphorylation of these transcription factors in their trans-activation domains leads to an increase in their ability to trans-activate transcription. p38-MAPKs also phosphorylate transcription factors (9) and activate MAPKAPK-2 and -3, which, in turn, phosphorylate the small HSPs (Hsp25/27) (22). The decreased expression of HSP72 in the genistein-pretreated PC hearts suggests a possible role of tyrosine phosphorylation in the synthesis of this protein as well. However, in the present study, we did not identify the exact signaling cascade that connects initiation of receptor tyrosine signaling, leading to the opening of the KATP channel and synthesis of HSP72. Future investigations using selective blockers of MAPK(s) would help in identifying the specific kinase(s) involved in the opening of the KATP channel or synthesis of HSP72 after PC.

The relationship of HSP72 synthesis and opening of the KATP channel in the development of late PC is not clear from these studies. HSP70 is the main chaperone molecule of all eukaryotic cells and plays a major role in facilitating the folding of newly synthesized proteins (27, 35). In the myocardium, heat-shock induced reduction in myocardial infarct size after I/R was associated with the activation of HSP accumulation as well as activation of the KATP channel in vivo (18, 43). Sadd and Hahn (46) observed the activation of voltage-dependent K+ channels after heating in a radiation-induced fibrosarcoma cell line; these currents were blocked by tetraethylammonium cations as well as modification of extracellular K+ currents. Negulyaev et al. (37) demonstrated that exogenous HSP70 resulted in an activation of outward currents through a K+-selective channel. Therefore, a possible role of HSP72 accumulation during late PC in the opening of the KATP channel during PC cannot be ruled out.

In summary, our results show that genistein blocks the delayed protective effect of late ischemic PC, as demonstrated by significantly increased infarct size. Shortening of the APD and synthesis of HSP72 were also blocked by genistein, suggesting that tyrosine phosphorylation may be involved in these processes. However, one must recognize that measurement of epicardial monophasic action potentials is a relatively crude technique for measuring changes in APD, especially in the critical areas of the ischemic myocardium. Therefore, additional detailed studies using patch-clamp as well as intracellular recording techniques will be required to further substantiate these results.


    ACKNOWLEDGEMENTS

This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-51045 and HL-59469 (to R. C. Kukreja). N. L. Bernardo was supported by a fellowship from the American Heart Association.


    FOOTNOTES

Address for reprint requests and other correspondence: R. C. Kukreja, Div. of Cardiology, Medical College of Virginia, Virginia Commonwealth Univ., 1101 E. Marshall St., Richmond, VA 23298 (E-mail: rakesh{at}hsc.vcu.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 31 March 2000; accepted in final form 8 June 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Arnoult, C, Lemos JR, and Florman HM. Voltage-dependent modulation of T-type calcium channels by protein tyrosine phosphorylation. EMBO J 16: 1593-1599, 1997[Web of Science][Medline].

2.   Baines, CP, Liu GS, Birincioglu M, Critz SD, Cohen MV, and Downey JM. Ischemic preconditioning depends on interaction between mitochondrial KATP channels and actin cytoskeleton. Am J Physiol Heart Circ Physiol 276: H1361-H1368, 1999[Abstract/Free Full Text].

3.   Baines, CP, Wang L, Cohen MV, and Downey JM. Protein tyrosine kinase is downstream of protein kinase C for ischemic preconditioning's anti-infarct effect in the rabbit heart. J Mol Cell Cardiol 30: 383-392, 1998[Web of Science][Medline].

4.   Baxter, GF, Goma FM, and Yellon DM. Involvement of PKC in the delayed cytoprotection following sublethal ischemia in rabbit myocardium. Br J Pharmacol 115: 222-224, 1995[Web of Science][Medline].

5.   Baxter, GF, and Yellon DM. ATP-sensitive K+ channels mediate the delayed cardioprotective effect of adenosine A1 receptor activation. J Mol Cell Cardiol 31: 981-989, 1999[Web of Science][Medline].

6.   Bedheit, SS, Restivo M, Boutjdir M, Henkin P, Gooyahdeh K, Assadi M, Khatib S, Gough WB, and El-Sherif N. Effects of glyburide on ischemia-induced changes in extracellular potassium and local myocardial activation: a potential new approach to the management of ischemia-induced malignant ventricular arrhythmias. Am Heart J 119: 1025-1033, 1990[Web of Science][Medline].

7.   Bernardo, NL, D'Angelo M, Okubo S, Joy A, and Kukreja RC. Second window of ischemic preconditioning is mediated by opening of ATP-sensitive potassium channels in the rabbit heart. Am J Physiol Heart Circ Physiol 276: H1323-H1330, 1999[Abstract/Free Full Text].

8.   Bernardo, NL, Okubo S, Maaieh M, Wood MA, and Kukreja RC. Delayed preconditioning with adenosine is mediated by opening of ATP-sensitive K+ channels in rabbit heart. Am J Physiol Heart Circ Physiol 277: H128-H135, 1999[Abstract/Free Full Text].

9.   Bogoyevitch, MA, Andersson MB, Gillespie-Brown J, Clerk A, Glennon PE, Fuller SJ, and Sugden PH. Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J 314: 115-121, 1996.

10.   Bogoyevitch, MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, Marshall CJ, and Sugden PH. Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart: p38/RK MAPK and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ Res 79: 162-173, 1996[Abstract/Free Full Text].

11.   Chen, CC, Wang JK, and Lin SB. Antisense oligonucleotides targeting protein kinase C-alpha, -beta I, or -delta but not -eta inhibit lipopolysaccharide-induced nitric oxide synthase expression in RAW 264.7 macrophages: involvement of a nuclear factor kappa B-dependent mechanism. J Immunol 161: 6206-6214, 1998[Abstract/Free Full Text].

12.   Dawn, B, Xuan YT, Qiu Y, Takano H, Tang XL, Ping P, Banerjee S, Hill M, and Bolli R. Bifunctional role of protein tyrosine kinases in late preconditioning against myocardial stunning in conscious rabbits. Circ Res 85: 1154-1163, 1999[Abstract/Free Full Text].

13.   Elliott, GT, Comerford ML, Smith JR, and Zhao L. Myocardial ischemia/reperfusion protection using monophosphoryl lipid A is abrogated by the ATP-sensitive potassium channel blocker, glibenclamide. Cardiovasc Res 32: 1071-1080, 1996[Abstract/Free Full Text].

14.   Fryer, RM, Hsu AK, Eells JT, Nagase H, and Gross GJ. Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels. Circ Res 84: 846-851, 2000[Abstract/Free Full Text].

15.   Fryer, RM, Schultz JE, Hsu AK, and Gross GJ. Pretreatment with tyrosine kinase inhibitors partially attenuates ischemic preconditioning in rat hearts. Am J Physiol Heart Circ Physiol 275: H2009-H2015, 1998[Abstract/Free Full Text].

16.   Garlid, KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, and Grover GJ. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res 81: 1072-1082, 1997[Abstract/Free Full Text].

17.   Grover, GJ, Dalonzo AJ, Parham CS, and Darbenzio RB. Cardioprotection with the KATP opener is not correlated with ischemic myocardial action potential duration. J Cardiovasc Pharmacol 26: 145-152, 1995[Web of Science][Medline].

18.   Hoag, JB, Qian YZ, Nayeem MA, D'Angelo M, and Kukreja RC. ATP-sensitive potassium channel mediates delayed ischemic protection by heat stress in rabbit heart. Am J Physiol Heart Circ Physiol 273: H861-H868, 1997[Abstract/Free Full Text].

19.   Imagawa, JI, Baxter GF, and Yellon DM. Genistein, a tyrosine kinase inhibitor, blocks the "second window of protection" 48 h after ischemic preconditioning in the rabbit. J Mol Cell Cardiol 29: 1885-1893, 1997[Web of Science][Medline].

20.   Janin, Y, Qian YZ, Hoag JB, Elliott GT, and Kukreja RC. Pharmacologic preconditioning with monophosphoryl lipid A is abolished by 5-hydroxydecanoate, a specific inhibitor of the KATP channel. J Cardiovasc Pharmacol 32: 337-342, 1998[Web of Science][Medline].

21.   Jonas, EA, and Kaczmarek LK. Regulation of potassium channels by protein kinases. Curr Opin Neurobiol 6: 318-323, 1996[Web of Science][Medline].

22.   Kawasaki, H, Morooka T, Shimohama S, Kimura J, Hirano T, Gotoh Y, and Nishida E. Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J Biol Chem 272: 18518-18521, 1997[Abstract/Free Full Text].

23.   Kim, J, Nueda A, Meng YH, Dynan WS, and Mivechi NF. Analysis of the phosphorylation of human heat shock transcription factor-1 by MAP kinase family members. J Cell Biochem 67: 43-54, 1997[Web of Science][Medline].

24.   Kukreja, RC, Qian YZ, Okubo S, and Flaherty EE. Role of protein kinase C and 72 kDa heat shock protein in ischemic tolerance following heat stress in the rat heart. Mol Cell Biochem 195: 123-131, 1999[Web of Science][Medline].

25.   Kuzuya, T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, and Tada M. Delayed effect of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res 72: 1293-1299, 1993[Abstract/Free Full Text].

26.   Levitan, IB. Modulation of ion channels by protein phosphorylation and dephosphorylation. Annu Rev Physiol 56: 193-212, 1994[Web of Science][Medline].

27.   Lindquist, S. The heat-shock response. Annu Rev Biochem 55: 1151-1191, 1986[Web of Science][Medline].

28.   Liu, Y, Sato T, O'Rourke B, and Marban E. Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation 97: 2463-2469, 1998[Abstract/Free Full Text].

29.   Marber, MS, Latchman DS, Walker JM, and Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation 88: 1264-1272, 1993[Abstract/Free Full Text].

30.   Marber, MS, Mestril R, Chi SH, Sayen R, Yellon DM, and Dillmann WH. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 95: 1446-1456, 1995.

31.   Maulik, N, Sato M, Price BD, and Das DK. An essential role of NFkappa B in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia. FEBS Lett 429: 365-369, 2000.

32.   Maulik, N, Watanabe M, Zu YL, Huang CK, Cordis GA, Schley JA, and Das DK. Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts. FEBS Lett 396: 233-237, 1996[Web of Science][Medline].

33.   Mei, DA, Elliot GT, and Gross GJ. KATP channels mediate late preconditioning against infarction produced by monophosphoryl lipid A. Am J Physiol Heart Circ Physiol 271: H2723-H2729, 1996[Abstract/Free Full Text].

34.   Molokanova, E, Trivedi B, Savchenko A, and Kramer RH. Modulation of rod photoreceptor cyclic nucleotide-gated channels by tyrosine phosphorylation. J Neurosci 17: 9068-9076, 1997[Abstract/Free Full Text].

35.   Morimoto, RI, Mosser D, McClanahan TK, Theodorakis NG, and Williams G. Stress-Induced Proteins. New York: Liss, 1993, p. 83-94.

36.   Murry, CE, Jennings RB, and Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124-1136, 1986[Abstract/Free Full Text].

37.   Negulyaev, YA, Vedernikova EA, Kinev AV, and Voronin AP. Exogenous heat shock protein hsp70 activates potassium channels in U937 cells. Biochim Biophys Acta 1282: 156-162, 1996[Medline].

38.   Ockaili, R, Emani VR, Okubo S, Brown M, Krottapalli K, and Kukreja RC. Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide. Am J Physiol Heart Circ Physiol 277: H2425-H2434, 1999[Abstract/Free Full Text].

39.   Okajima, F, Akbar M, Abdul Majid M, Sho K, Tomura H, and Kondo Y. Genistein, an inhibitor of protein tyrosine kinase, is also a competitive antagonist for P1-purinergic (adenosine) receptor in FRTL-5 thyroid cells. Biochem Biophys Res Commun 203: 1488-1495, 1994[Web of Science][Medline].

40.   Okubo, S, Bernardo NL, Jao AB, Elliott GT, and Kukreja RC. Tyrosine phosphorylation is involved in second window of preconditioning in rabbit heart (Abstract). Circulation 96, Suppl: I313, 1997.

41.   Okubo, S, Xi L, Bernardo NL, Yoshida K, and Kukreha RC. Myocardial preconditioning: basic concepts and potential mechanisms. Mol Cell Biochem 196: 3-12, 1999[Web of Science][Medline].

42.   Paillart, C, Carlier E, Guedin D, Dargent B, and Couraud F. Direct block of voltage-sensitive sodium channels by genistein, a tyrosine kinase inhibitor. J Pharmacol Exp Ther 280: 521-526, 1997[Abstract/Free Full Text].

43.   Pell, TJ, Yellon DM, Goodwin RW, and Baxter GF. Myocardial ischemic tolerance following heat stress is abolished by ATP-sensitive potassium channel blockade. Cardiovasc Drugs Ther 11: 679-686, 1997[Web of Science][Medline].

44.   Ping, P, Zhang J, Cao X, Li RC, Kong D, Tang XL, Qiu Y, Manchikalapudi S, Auchampach JA, Black RG, and Bolli R. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. Am J Physiol Heart Circ Physiol 276: H1468-H1481, 1999[Abstract/Free Full Text].

45.   Qian, YZ, Bernardo NL, Nayeem MA, Chelliah J, and Kukreja RC. Induction of 72-kDa heat shock protein does not produce second window of ischemic precondiitoning in rat heart. Am J Physiol Heart Circ Physiol 276: H224-H234, 1999[Abstract/Free Full Text].

46.   Saad, AH, and Hahn GM. Activation of potassium channels: relationship to the heat shock response. Proc Natl Acad Sci USA 89: 9396-9399, 1992[Abstract/Free Full Text].

47.   Sasaki, N, Sato T, Ohler A, O'Rourke B, and Marban E. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation 101: 439-445, 2000[Abstract/Free Full Text].

48.   Sato, T, O'Rourke B, and Marban E. Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res 83: 110-114, 1998[Abstract/Free Full Text].

49.   Siegelbaum, SA. Channel regulation. Ion channel control by tyrosine phosphorylation. Curr Biol 4: 242-245, 1994[Web of Science][Medline].

50.   Smart, TG. Regulation of excitatory and inhibitory neurotransmitter-gated ion channels by protein phosphorylation. Curr Opin Neurobiol 7: 358-367, 1997[Web of Science][Medline].

51.   Takashi, E, Wang Y, and Ashraf M. Activation of mitochondrial KATP channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway. Circ Res 85: 1146-1153, 1999[Abstract/Free Full Text].

52.   Wilson, GF, and Kaczmarek LK. Mode-switching of a voltage-gated cation channel is mediated by a protein kinase A-regulated tyrosine phosphatase. Nature 366: 433-438, 1993[Medline].

53.   Yao, Z, and Gross GJ. Effects of the KATP channel opener bimakalim on coronary blood flow, monophasic action potential duration, and infarct size in dogs. Circulation 89: 1769-1775, 1994[Abstract/Free Full Text].

Am J Physiol Heart Circ Physiol 279(5):H2269-H2276
0363-6135/00 $5.00 Copyright © 2000 the American Physiological Society


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
S. Okubo, Y. Tanabe, K. Takeda, M. Kitayama, S. Kanemitsu, R. C. Kukreja, and N. Takekoshi
Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of {delta}-opioid receptor
Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1786 - H1791.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
C. R. Hampton, A. Shimamoto, C. L. Rothnie, J. Griscavage-Ennis, A. Chong, D. J. Dix, E. D. Verrier, and T. H. Pohlman
HSP70.1 and -70.3 are required for late-phase protection induced by ischemic preconditioning of mouse hearts
Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H866 - H874.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
B. Dawn, H. Takano, X.-L. Tang, E. Kodani, S. Banerjee, A. Rezazadeh, Y. Qiu, and R. Bolli
Role of Src protein tyrosine kinases in late preconditioning against myocardial infarction
Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H549 - H556.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
T. C. Zhao, D. S. Hines, and R. C. Kukreja
Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial KATP channels
Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1278 - H1285.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
T. C. Zhao, M. M. Taher, K. C. Valerie, and R. C. Kukreja
p38 Triggers Late Preconditioning Elicited by Anisomycin in Heart: Involvement of NF-{kappa}B and iNOS
Circ. Res., November 9, 2001; 89(10): 915 - 922.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (12)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Okubo, S.
Right arrow Articles by Kukreja, R. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Okubo, S.
Right arrow Articles by Kukreja, R. C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online