Skip Navigation

Cardiovascular Research 1998 40(2):251-256; doi:10.1016/S0008-6363(98)00187-4
© 1998 by European Society of Cardiology
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Woodcock, E. A
Right arrow Articles by Binah, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Woodcock, E. A
Right arrow Articles by Binah, O.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 1998, European Society of Cardiology

Ins(1,4,5)P3 and cardiac dysfunction

Elizabeth A Woodcocka,*, Scot J Matkovicha and Ofer Binahb

aCellular Biochemistry Laboratory, Baker Medical Research Institute, Commercial Road, Prahran, Victoria, Australia
bRappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine, The Bernard Katz Center for Cell Biophysics, Technion—Israel Institute of Technology, Haifa, Israel

* Corresponding author. Tel.: +61-3-9522-4387; Fax: +61-3-9521-1362; E-mail: liz.woodcock@baker.edu.au

Received 18 February 1998; accepted 26 May 1998

KEYWORDS Arrhythmia (mechanisms); Calcium (cellular); Signal transduction; Reperfusion; Immunology


   1 Introduction
Top
 1 Introduction
2 Inflammatory heart disease
 3 Ischaemia and reperfusion
 4 Heart failure
 5 Summary and conclusions
 References
 
Cardiac related death occurs rapidly via the development of arrhythmias or more slowly by a progressive decline in mechanical performance reflecting decreased contractile activity as well as loss of viable myocytes. Pathological conditions such as myocardial ischaemia, inflammatory heart diseases and various forms of heart failure are associated with both sudden death and also with a more progressive decrease in cardiac function. Electrophysiological disturbances leading to malignant ventricular arrhythmias are the usual cause of sudden cardiac death, whereas a gradual loss of functional myocytes, or a decline in their performance, underlies heart failure ultimately leading to cardiac decompensation. The mechanisms initiating these scenarios are complex and multifactorial, involving both extracellular and intracellular factors. However, given the continued major contribution of cardiac deaths to overall mortality, understanding the processes which initiate these pathological events is of prime importance. The current review will focus on changes in the intracellular milieu and in particular the potential role of the Ca2+-releasing second messenger inositol(1,4,5)trisphosphate [Ins(1,4,5)P3] in initiating arrhythmias and cell death in cardiac pathologies.

Ins(1,4,5)P3 is generated along with sn-1,2-diacylglycerol following the activation of either G protein-coupled receptors and phospholipase C-β (PLC-β) isoforms or receptor tyrosine kinases and PLC-{gamma} isoforms [1]. The Ins(1,4,5)P3 which is rapidly released into the cytoplasm, especially after activation of G protein-coupled receptors, activates Ins(1,4,5)P3 receptors on Ca2+ stores in the endoplasmic reticulum [sarcoplasmic reticulum (SR) in muscle cells] causing a rapid and quantal release of Ca2+ [2]. In most non-cardiac cell types, this Ins(1,4,5)P3-initiated Ca2+ response can be perpetuated by the process of Ca2+-induced Ca2+ release mediated by either the Ins(1,4,5)P3 receptors or the related family of ryanodine receptors, the overall effect of this being that the Ca2+ signal within the cell is regulated spatially as well as quantitatively [3, 4].

Instead of being primarily regulated by receptors coupled to Ins(1,4,5)P3 generation, in heart the control of Ca2+ and hence the contractile state of the myocytes is predominantly regulated by the electrical activity of the sarcolemma. The cardiac action potential is initiated by depolarization of the sarcolemma and sustained in the plateau phase by the activation of voltage-gated L type Ca2+ channels (ICa,L). This in turn leads to a subsequent release of Ca2+ from the ryanodine receptor-operated stores of the SR. The Ca2+ released from the SR binds to troponin-C and activates the coupling of actin to myosin, resulting in contraction of myofilaments. Removal of Ca2+ from the cytosol is accomplished by means of several mechanisms including the sarcolemmal Na+–Ca2+ exchanger and the Ca2+-ATPases of the sarcolemma and the SR. None of these processes involve Ins(1,4,5)P3, and factors which activate PLC, such as {alpha}1-adrenergic agonists and endothelin, are not major regulators of cardiac function under physiological conditions. In comparison with the cardiac ryanodine receptors, Ins(1,4,5)P3 receptors in heart tissue respond only weakly to Ins(1,4,5)P3 and release Ca2+ slowly [5]. It is probably this slow release which prevents the Ca2+ generated by Ins(1,4,5)P3 from inducing Ca2+-induced Ca2+ release. Instead, the Ca2+ generated by Ins(1,4,5)3 has been reported to initiate slow Ca2+ oscillations [6]. Such slow increases in [Ca2+]i potentially have at least three acute effects on the cardiac action potential. First, it can stimulate a transient inward current (Iti) evoking delayed afterdepolarizations so that triggered activity can develop in otherwise quiescent ventricular muscle [7, 8]. Second, the slowing of repolarization caused by elevated [Ca2+]i can favour conditions for reentry [9]. Third, it can cause intercellular uncoupling with conduction slowing [10–13]. Any of these alterations in myocardial electrical activity are potentially proarrhythmic and furthermore, Ins(1,4,5)P3 has been reported to activate Na+–Ca2+ exchange, which might also be expected to increase the likelihood of arrhythmias, especially under ischaemic or reperfusion conditions [14].

In addition to these direct effects, elevated [Ca2+]i can affect myocyte function indirectly by activating a variety of intracellular components such as Ca2+-dependent protein kinases, phosphatases, proteases and endonucleases [15, 16]. Such actions are likely responsible for the more chronic effects of Ca2+ overload. Ins(1,4,5)P3 has been reported to be required for signalling pathways leading to apoptotic cell death in lymphoid cells [17, 18]when apoptosis was induced by a number of different agents including ionizing radiations, Fas activation and glucocorticoids [19]. The requirement for functional Ins(1,4,5)P3 receptors for apoptotic signalling under these conditions points to a need either for elevated cytosolic Ca2+ or depletion of intracellular stores. However, not all apoptotic pathways appear to utilise intermediates which interact with Ca2+ stores. For recent reviews on signalling pathways in apoptosis see Refs. [20–23].


   2 Inflammatory heart disease
Top
 1 Introduction
 2 Inflammatory heart disease
3 Ischaemia and reperfusion
 4 Heart failure
 5 Summary and conclusions
 References
 
Immunological mechanisms are involved in a variety of cardiac pathologies including heart transplant rejection, myocarditis (and the resulting dilated cardiomyopathy) as well as Chagas' heart disease [24, 25]. These diseases are characterised by lymphocyte infiltration, a decline in cardiac performance, due in part to loss of viable myocytes, and life-threatening arrhythmias. Many of these effects can be mimicked in isolated cardiomyocyte preparations. Addition of activated cytotoxic T lymphocytes to isolated cardiomyocytes caused the generation of electrophysiological disturbances, primarily prolongation of action potential duration, and associated early afterdepolarizations which were followed by Ca2+ overload, hypercontracture and cell death. These responses could be prevented either by using U-73122, an inhibitor of PLC, or by blocking the Ins(1,4,5)P3 receptor with heparin [26]. Cytocidal lymphocytes posses two distinct lytic mechanisms [27]. One of these involves perforins which create transmembrane pores allowing the entry of granzymes secreted by the lymphocytes. The second pathway involves the Fas ligand expressed on the surface of the lymphocytes binding to the Fas (receptor) (CD95/Apo-1) and activating apoptotic pathways similar to those initiated by TNF-{alpha} [20, 28]. Using cytotoxic T lymphocytes from perforin knockout mice, activation of Fas was shown to account for perforin-independent myocyte damage. Direct activation of Fas caused [Ca2+]i overload associated with afterdepolarizations, followed by eventual cell death. Once again, inhibition of the Ins(1,4,5)P3 pathway prevented all of these changes [29]. In support of these findings, adding PLC to guinea-pig ventricular myocytes was shown to cause functional alterations resembling those seen in myocytes conjugated to cytotoxic T lymphocytes, including a reduction of the resting potential, induction of delayed afterdepolarizations, increased [Ca2+]i and cell destruction [30]. These studies pointed to Ins(1,4,5)P3 as a prime initiator of cardiomyocyte damage, being involved in the short term in the generation of arrhythmias, and with longer exposure in cell death pathways. The data also suggest that Fas activation causes an increase in either Ins(1,4,5)P3 content or in myocyte sensitivity to Ins(1,4,5)P3. To date, Fas has not been shown to directly cause generation of Ins(1,4,5)P3. It does not appear to bind PLC-{gamma} nor to interact with G proteins to activate PLC-β isoforms [23]. However, addition of activating anti-Fas antibodies to cardiomyocytes caused Ins(1,4,5)P3-dependent action potential disturbances that preceded hypercontracture and cell death [29]. This argues against a late increase in Ins(1,4,5)P3 following Ca2+ overload and apoptotic death. This scenario therefore suggests that Ins(1,4,5)P3 generation initiates changes in Ca2+ which, in turn, cause electrophysiological disturbances resulting in further Ca2+ overload and eventual cell dysfunction. More definitive evidence for this was supplied by experiments in which Ins(1,4,5)P3 was added to myocytes intracellularly and was shown to mimic the effects of Fas activation on action potential characteristics. Importantly, the inactive isomer, Ins(1,3,4)P3 did not cause either action potential changes or cell death [29]. These experiments and their findings are shown diagrammatically in Fig. 1.


Figure 1
View larger version (26K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Initiation of electrophysiological disturbances ({Delta}V) and apoptosis by Fas activation in cardiomyocytes. Inhibition of Ins(1,4,5)P3 generation by U-73122 or of its interaction with its receptor by heparin abolished the effects of Fas activation. In addition, direct intracellular application of Ins(1,4,5)P3 [but not Ins(1,3,4)P3] mimicked the effects of Fas. The mechanisms by which Fas activates the Ins(1,4,5)P3 response pathway are currently unknown.

 
The requirement for Ins(1,4,5)P3 receptor activation for Fas-induced cardiomyocyte death is reminiscent of earlier studies in lymphocytes. These studies reported resistance to apoptosis in cells deficient in the type-3 [17]or type-1 receptor [19]. The type-3 receptor in lymphocytes is largely plasmalemmal whereas the type-1 receptor resides on the endoplasmic reticulum. Thus, while implying a role for Ca2+ in the apoptotic response, these studies identified different mechanisms as being responsible for regulating the Ca2+ levels. However, a number of studies have reported a relationship between apoptosis and depletion of intracellular Ca2+ stores without a requirement for entry of extracellular Ca2+ [31, 32]. While a number of studies have reported that the type-1 receptor predominates in heart [18, 33, 34], recent studies have presented evidence that the type-2 receptor is most abundant in the cardiomyocytes [35].

Not all studies have demonstrated a requirement for rises in cytosolic Ca2+ or depletion of Ca2+ stores and why Ca2+ should be required for apoptosis under some conditions and not others is not clear. Some of the enzymes involved are Ca2+ requiring, especially the nucleases [36]and transglutaminases [37], but these are unlikely to be of central importance in the early stages of the response. The pathways involved in apoptotic death following Fas activation are diverse [22, 23]. The death domain of activated Fas binds adapter proteins which in turn activate caspases (cysteine proteases). These are primarily responsible for the activation of nucleases and the destruction of important signalling and structural proteins. Activated Fas also signals to the stress-activated protein kinase, c-Jun N-terminal kinase, which can in turn initiate caspase activation [38]. Furthermore, Fas also causes the generation of ceramide, which has been reported to activate Ras, raising the possibility of initiating multiple signalling pathways [39]. The contributions of these various pathways to apoptotic and anti-apoptotic responses most likely vary between cell types and which are involved in Fas-mediated apoptosis in cardiomyocytes is currently unknown.

Another important question is whether the electrophysiological changes observed after activation of cardiomyocyte Fas receptors are required for apoptosis or whether these reflect two separate detrimental responses. Ins(1,4,5)P3 has also been reported to be essential for apoptosis in non-excitable cells [17, 19], suggesting that electrophysiological changes are not an absolute requirement for apoptosis. However, in heart electrophysiological disturbances might serve to further increase the Ca2+ overload and thus potentiate the cell death pathway. This possibility is illustrated by the broken arrow in Fig. 2.


Figure 2
View larger version (22K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Electrophysiological and apoptotic responses to elevated Ins(1,4,5)P3. The possibility that alterations in electrical control mechanisms enhance Ca2+ overload and thus contribute to apoptosis is indicated by the broken arrow.

 

   3 Ischaemia and reperfusion
Top
 1 Introduction
 2 Inflammatory heart disease
 3 Ischaemia and reperfusion
4 Heart failure
 5 Summary and conclusions
 References
 
Reduction of the blood supply to the heart (ischaemia) and the re-introduction of flow (reperfusion) are associated with the development of arrhythmias [40, 41]and with myocyte death, partly due to apoptosis [42]. Arrhythmias occurring acutely during ischaemia and reperfusion are often associated with an activation of the sympathetic nervous system and there is evidence for linkage to stimulation of {alpha}1-adrenergic receptors [40, 43]. In addition, thrombin has been shown to be directly proarrhythmic under these pathological conditions by mechanisms unrelated to its coagulant activity [44, 45]. The finding of proarrhythmic activity of {alpha}1-adrenergic agonists and thrombin, only under ischaemic and reperfusion conditions, suggests some perturbation of the signalling pathways activated by {alpha}1-receptors and thrombin receptors in the myocardium under these conditions.

Both {alpha}1-adrenergic receptors and thrombin receptors in heart are coupled to phosphatidylinositol (PtdIns) turnover and thus their stimulation has the potential to generate Ins(1,4,5)P3. While neither of these effectors causes rapid changes in Ins(1,4,5)P3 content under physiological conditions, under conditions of early reperfusion, i.e., within 5 min of re-initiation of flow, large quantities of Ins(1,4,5)P3 are generated in the presence of either {alpha}1-receptor or thrombin receptor activation in hearts perfused with blood-free medium [45, 46].

Two different experimental approaches suggest a relationship between the generation of Ins(1,4,5)P3 and the development of reperfusion arrhythmias. First, there was a close correlation between the potencies of aminoglycosides and polyamines (which bind to the precursor lipid PtdIns(4,5)P2) in inhibiting Ins(1,4,5)P3 responses during reperfusion and their potencies in preventing the development of arrhythmias under these conditions [47]. Second, the Ins(1,4,5)P3 and arrhythmogenic responses to thrombin were inhibited by the PLC inhibitor U-73122 whereas those initiated by stimulation of {alpha}1-receptors were not [45]. The selectivity of the anti-arrhythmic activity of U-73122 to arrhythmias initiated by thrombin provided strong evidence that Ins(1,4,5)P3 generation is necessary for the development of arrhythmias during early reperfusion (Fig. 3). It is of interest that in addition to preventing reperfusion arrhythmias, the aminoglycoside streptomycin has been shown to prevent arrhythmias caused by wall stress [48], a perturbation which results in generation of Ins(1,4,5)P3 [49–52].


Figure 3
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Inhibition of Ins(1,4,5)P3 generation and of arrhythmogenic activity by gentamicin and U-73122 under conditions of post-ischaemic reperfusion. Gentamicin, which binds the precursor lipid PtdIns(4,5)P2, is not agonist selective, whereas U-73122 only affects responses initiated by thrombin receptors.

 
In addition to acute arrhythmias, reperfusion of ischaemic myocardium is also associated with substantial myocyte cell death, especially when longer reperfusion periods are studied [53]. Much of this cell death appears to be apoptotic [42, 54, 55], but it remains to be determined whether, like the apoptosis initiated by immunological mediators, it can be prevented by inhibitors of the Ins(1,4,5)P3 pathway. The transient nature of the Ins(1,4,5)P3 response in reperfusion might argue against its importance in responses requiring longer periods of ischaemia and reperfusion. However, there are two possible scenarios in which Ins(1,4,5)P3 might have a central role in this process. First, it is conceivable that the transient rise in Ins(1,4,5)P3 initiates disturbances in Ca2+ homeostasis which are self-perpetuating and cause a worsening Ca2+ overload, leading eventually to apoptotic death. Second, there have been a number of reports that reperfusion can lead to an upregulation of Fas expression both in vivo [55]and in isolated cardiomyocytes [56]. In the in vivo (blood perfused) heart, monocytes and neutrophils invade ischaemic and reperfused myocardium [57]but whether cells expressing Fas ligand (primarily T lymphocytes) also accumulate in reperfused myocardium has not yet been established. However, the increase in interleukin-6 under these conditions, makes this not unlikely [58].

Given the apparent requirement for Ins(1,4,5)P3 in apoptosis in other cell types and its role in Fas-mediated responses in cardiomyocytes, more studies of Ins(1,4,5)P3 involvement in cell death during myocardial ischaemia and reperfusion are warranted.


   4 Heart failure
Top
 1 Introduction
 2 Inflammatory heart disease
 3 Ischaemia and reperfusion
 4 Heart failure
5 Summary and conclusions
 References
 
Heart failure can result from chronic inflammation and prolonged ischaemia as well as from sustained pressure overload. The contributing factors are not always clearly defined because hearts damaged by ischaemic insult or hypertrophied in response to pressure overload are commonly infiltrated by inflammatory cells including Fas-expressing cytotoxic T lymphocytes [59]. The failing myocardium is sensitive to the development of arrhythmias [60, 61]and undergoes myocyte death both by necrotic and apoptotic mechanisms [62]. As described earlier for ischaemic and reperfusion conditions, the failing myocardium also experiences an increase in the relative activity of {alpha}1-adrenergic receptors but the mechanisms involved are likely different and derive primarily from a marked reduction in β-adrenergic activity [63]resulting in an increase in the relative importance of {alpha}1-receptor-mediated responses. The role of {alpha}1-receptors in the initiation of cardiac hypertrophy, in the neonatal cardiomyocyte model as well as in rat heart in vivo is well established [64–66]and recent studies have pointed to a substantial role of Gq, the G protein mediating {alpha}1-receptor activated Ins(1,4,5)P3 generation, in the development of hypertrophy and subsequent heart failure in vivo [67]. There is, as yet, no direct evidence for enhanced generation of Ins(1,4,5)P3 in failing myocardium, but indirect evidence for an alteration in Ins(1,4,5)P3 responsiveness has been presented. Transplanted hearts from patients with dilated cardiomyopathies expressed higher levels of mRNA encoding Ins(1,4,5)P3 receptors compared with well matched non-failing controls [68]. Increased Ins(1,4,5)P3 receptor content could potentially increase the sensitivity of the failing myocardium to Ins(1,4,5)P3 and thus sensitize the myocardium to arrhythmias and cell death initiated by Ins(1,4,5)P3.


   5 Summary and conclusions
Top
 1 Introduction
 2 Inflammatory heart disease
 3 Ischaemia and reperfusion
 4 Heart failure
 5 Summary and conclusions
References
 
There is now substantial evidence that Ins(1,4,5)P3, by virtue of its role in Ca2+ release, can initiate electrophysiological disturbances which develop into cardiac arrhythmias, and in addition appears to be involved in the progression of the cardiomyocytes to apoptosis. Therapeutic regimens targeting the generation or the actions of Ins(1,4,5)P3 may thus prove beneficial in treating or preventing a number of different cardiac pathologies.

Time for primary review 33 days.


   References
Top
 1 Introduction
 2 Inflammatory heart disease
 3 Ischaemia and reperfusion
 4 Heart failure
 5 Summary and conclusions
 References
 

  1. Berridge M.J. Inositol triphosphate and diacylglycerol: two interacting second messengers. Ann Rev Biochem (1987) 56:159–193.[Web of Science][Medline]
  2. Berridge M.J, Dupont G. Spatial and temporal signalling by calcium. Curr Opin Cell Biol (1994) 6:267–274.[CrossRef][Web of Science][Medline]
  3. Berridge M.J. Elementary and global aspects of calcium signalling—Annual Review Prize Lecture. J Physiol (London) (1997) 499:291–306.[Free Full Text]
  4. Berridge M. The AM and FM of calcium signalling. Nature (1997) 286:759–760.
  5. Kentish J.C, Barsotti R.J, Lea T.J, et al. Calcium release from cardiac sarcoplasmic reticulum induced by photorelease of calcium or Ins(1,4,5)P3. Am J Physiol (1990) 258:H610–H615.[Web of Science][Medline]
  6. Zhu Y, Nosek T.M. Inositol trisphosphate enhances Ca2+ oscillations but not Ca2+-induced Ca2+ release from cardiac sarcoplasmic reticulum. Pflugers Arch (1991) 418:1–6.[CrossRef][Web of Science][Medline]
  7. Kass R.S, Lederer W.J, Tsien R.W, Weingart R. Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibers. J Physiol (London) (1978) 281:187–208.[Abstract/Free Full Text]
  8. Lederer W.J, Tsien R.W. Transient inward current underlying arrhythmogenic effects of cardiotonic steroids in Purkinje fibers. J Physiol (London) (1976) 263:73–100.[Abstract/Free Full Text]
  9. Kleber A, Fast V. Molecular and cellular aspects of re-entrant arrhythmias. Basic Res Cardiol (1997) 92(Suppl. 1):111–119.[CrossRef][Web of Science][Medline]
  10. de Mello W.C. Effect of intracellular injection of calcium and strontium in cell communication in heart. J Physiol (London) (1975) 250:231–245.[Abstract/Free Full Text]
  11. de Mello W.C. Cell-to-cell communication in heart and other tissues. Prog Biophys Mol Biol (1982) 39:147–182.[Web of Science][Medline]
  12. Burt J.M. Block of intracellular communication: interaction of intracellular H+ and Ca2+. Am J Physiol (1987) 253:C607–C612.[Web of Science][Medline]
  13. White R.L, Doeller J.E, Verselis V.K, Wittenberg B.A. Gap junctional conductance between pairs of ventricular myocytes is modulated synergistically by H+ and Ca++. J Gen Physiol (1990) 95:1061–1075.[Abstract/Free Full Text]
  14. Gilbert J.C, Shirayama T, Pappano A.J. Inositol trisphosphate promotes Na–Ca exchange current by releasing calcium from sarcoplasmic reticulum in cardiac myocytes. Circ Res (1991) 69:1632–1639.[Abstract/Free Full Text]
  15. Orrenius S, Nicotera P. The calcium ion and cell death. J Neural Transm (1994) 43:1–11.[Medline]
  16. McConkey D, Hartzell P, Duddy S, Hakansson H, Orrenius S. Tetrachloridebenzo-p-dioxin kills immature thymocytes by Ca2+-mediated endonuclease activation. Science (1988) 242:256–259.[Abstract/Free Full Text]
  17. Khan A.A, Soloski M.J, Sharp A.H, et al. Lymphocyte apoptosis: mediation by increased type 3 inositol 1,4,5-trisphosphate receptor. Science (1996) 273:503–507.[Abstract]
  18. Marks A. Intracellular calcium-release channels: regulators of cell life and death. Am J Physiol (1997) 272:H597–H605.[Web of Science][Medline]
  19. Jayaraman T, Marks A.R. T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis. Mol Cell Biol (1997) 17:3005–3012.[Abstract]
  20. Pulkki K.J. Cytokines and cardiomyocyte death. Ann Med (1997) 29:339–343.[Web of Science][Medline]
  21. MacLellan W.R, Schneider M.D. Death by design—programmed cell death in cardiovascular biology and disease. Circ Res (1997) 81:137–144.[Abstract/Free Full Text]
  22. Park D.S, Stefanis L, Greene L.A. Ordering the multiple pathways of apoptosis. Trend Cardiovasc Med (1997) 7:294–301.[CrossRef][Web of Science]
  23. Eischen C.M, Leibson P.J. The Fas pathway in apoptosis. Adv Pharmacol (1997) 41:107–132.[Medline]
  24. Barry W. Mechanisms of immune-mediated myocyte injury. Circulation (1994) 89:2421–2432.[Abstract/Free Full Text]
  25. Binah O. Immune effector mechanisms in heart transplant rejection. Cardiovasc Res (1994) 28:1748–1757.[Abstract/Free Full Text]
  26. Felzen B, Berke G, Gardner P, Binah O. Involvement of the IP3 cascade in the damage to guinea-pig ventricular myocytes induced by cytotoxic T lymphocytes. Pflugers Arch (1997) 433:721–726.[CrossRef][Web of Science][Medline]
  27. Berke G. The Fas-based mechanism of lymphocytotoxicity. Hum Immunol (1997) 54:1–7.[CrossRef][Web of Science][Medline]
  28. Berridge M.J. Lymphocyte activation in health and disease. Crit Rev Immunol (1997) 17:155–178.[Web of Science][Medline]
  29. Felzen B, Shilkrut M, Less H, et al. Fas (CD95/Apo-1)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin gene-knockout mice: involvement of inositol trisphosphate. Circ Res (1998) 82:438–450.[Abstract/Free Full Text]
  30. Hayashi H, Nyiata H, Terada H, et al. Effect of phospholipase C on action potential and intracellular Ca2+ concentrations in guinea pig heart. Jpn Circ J (1993) 57:344–353.[Medline]
  31. He H, Lam M, McCormick T.S, Distelhorst C.W. Maintenance of calcium homeostasis in the endoplasmic reticulum by Bcl-2. J Cell Biol (1997) 138:1219–1228.[Abstract/Free Full Text]
  32. Bian X, Hughes F.M Jr., Huang Y, Cidlowski J.A, Putney J.W Jr. Roles of cytoplasmic Ca2+ and intracellular Ca2+ stores in induction and suppression of apoptosis in S49 cells. Am J Physiol (1997) 272:C1241–1249.[Web of Science][Medline]
  33. Gorza L, Schiaffino S, Volpe P. Inositol 1,4,5-trisphosphate receptor in heart—evidence for its concentration in Purkinje myocytes of the conduction system. J Cell Biol (1993) 121:345–353.[Abstract/Free Full Text]
  34. Kijima Y, Saito A, Jetton T.L, Magnuson M.A, Fleischer S. Different intracellular localization of inositol 1,4,5-trisphosphate and ryanodine receptors in cardiomyocytes. J Biol Chem (1993) 268:3499–3506.[Abstract/Free Full Text]
  35. Perez P.J, Ramos-Franco J, Fill M, Mignery G.A. Identification and functional reconstitution of the type 2 inositol 1,4,5-trisphosphate receptor from ventricular cardiac myocytes. J Biol Chem (1997) 272:23961–23969.[Abstract/Free Full Text]
  36. Moretta A. Molecular mechanisms in cell-mediated cytotoxicity. Cell (1997) 90:13–18.[CrossRef][Web of Science][Medline]
  37. Balajthy Z, Kedei N, Nagy L, Davies P.J.A, Fesus L. Lack of induction of tissue transglutaminase but activation of the preexisting enzyme in c-Myc-induced apoptosis of CHO cells. Biochem Biophys Res Commun (1997) 236:280–284.[CrossRef][Web of Science][Medline]
  38. Toyoshima F, Moriguchi T, Nishida E. Fas induces cytoplasmic apoptotic responses and activation of the MKK7-JNK/SAPK and MKK6-038 pathways independent of CPP32-like proteases. J Cell Biol (1997) 139:1005–1014.[Abstract/Free Full Text]
  39. Gulbins E, Brenner B, Koppenhoefer U, Linderkamp O, Lang F. Fas or ceramide induce apoptosis by Ras-regulated phosphoinositide-3-kinase activation. J Leukocyte Biol (1998) 63:253–263.[Abstract]
  40. Sheridan D.J. Alpha adrenoceptors and arrhythmias. J Mol Cell Cardiol (1986) 18:59–68.[Medline]
  41. Kinoshita K, Hearse D, Braimbridge M, Manning A. Ischemia- and reperfusion-induced arrhythmias in conscious rats. Jpn Circ J (1988) 52:1384–1392.[Medline]
  42. Gottlieb R.A, Burleson K.O, Kloner R.A, Babior B.M, Engler R.L. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest (1994) 94:1621–1628.[Web of Science][Medline]
  43. Kurz T, Yamada K, DaTorre S, Corr P. Alpha1-adrenergic system and arrhythmias in ischaemic heart disease. Eur Heart J (1991) 12:88–98.[Abstract/Free Full Text]
  44. Goldstein J, Michelle M, Butterfield C, et al. Arrhythmogenic influence of intracoronary thrombosis during acute myocardial ischemia. Circulation (1994) 90:139–147.[Abstract/Free Full Text]
  45. Jacobsen A.N, Du X.J, Lambert K.A, Dart A.M, Woodcock E.A. Arrhythmogenic action of thrombin during myocardial reperfusion via release of inositol 1,4,5-triphosphate. Circulation (1996) 93:23–26.[Abstract/Free Full Text]
  46. Anderson K, Dart A, Woodcock E. Inositol phosphate release and metabolism during myocardial ischemia and reperfusion in rat heart. Circ Res (1995) 76:261–268.[Abstract/Free Full Text]
  47. Du X.-J, Anderson K, Jacobsen A, Woodcock E, Dart A. Suppression of ventricular arrhythmias during ischaemia–reperfusion by agents inhibiting Ins(1,4,5)P3 release. Circulation (1995) 91:2712–2716.[Abstract/Free Full Text]
  48. Salmon A, Mays J, Dalton G, Jones J, Levi A. Effect of streptomycin on wall-stress-induced arrhythmias in working rat heart. Cardiovasc Res (1997) 34:493–503.[Abstract/Free Full Text]
  49. Dassouli A, Sulpice J.C, Roux S, Crozatier B. Stretch-induced inositol trisphosphate and tetrakisphosphate production in rat cardiomyocytes. J Mol Cell Cardiol (1993) 25:973–982.[CrossRef][Web of Science][Medline]
  50. von Harsdorf R, Lang R, Fullerton M, Smith A, Woodcock E. Right atrial dilatation increases inositol-(1,4,5)trisphosphate accumulation: implications for the control of atrial natriuretic peptide secretion. FEBS Lett (1988) 233:201–215.[CrossRef][Web of Science][Medline]
  51. von Harsdorf R, Lang R, Fullerton M, Woodcock E.A. Myocardial stretch stimulates phosphatidylinositol turnover. Circ Res (1989) 65:494–501.[Abstract/Free Full Text]
  52. Paul K, Ball N, Dorn G, Walsh R. Left ventricular stretch stimulates angiotensin II-mediated phosphatidylinositol hydrolysis and protein kinase C{epsilon} isoform translocation in adult guinea pig hearts. Circ Res (1997) 81:643–650.[Abstract/Free Full Text]
  53. Piot C.A, Padmanaban D, Ursell P.C, Sievers R.E, Wolfe C.L. Ischemic preconditioning decreases apoptosis in rat hearts in vivo. Circulation (1997) 96:1598–1604.[Abstract/Free Full Text]
  54. Piot C, Wolfe C. Apoptosis: a new mechanism of lethal myocyte reperfusion injury? J Throm Thrombol (1997) 4:67–68.[CrossRef]
  55. Kajstura J, Cheng W, Reiss K, et al. Apoptotic and necrotic myocyte deaths are independent contributing variables of infarct size in rats. Lab Invest (1996) 74:86–107.[Web of Science][Medline]
  56. Tanaka M, Ito H, Akimoto S, et al. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res (1994) 75:426–433.[Abstract/Free Full Text]
  57. Birdsall H, Green D, Trial J, et al. Complement C5a, TGF-b1, and MCP-1, in sequence, induce migration of monocytes into ischemic canine myocardium within the first one to five hours after reperfusion. Circulation (1997) 95:684–692.[Abstract/Free Full Text]
  58. Sharma H.S, Das D.K. Role of cytokines in myocardial ischemia and reperfusion. Mediators Inflamm (1997) 6:175–183.[Medline]
  59. Limas C. Cardiac autoantibodies in dilated cardiomyopathy. Circulation (1997) 95:1979–1980.[Free Full Text]
  60. Pogwizd S.M. Nonreentrant mechanisms underlie spontaneously occurring ventricular arrhythmias in dilated cardiomyopathy (Abstract). Circulation (1993) 88:I326.
  61. Pogwizd S.M, Hoyt R.H, Saffitz J.E, et al. Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart. Circulation (1992) 86:1872–1887.[Abstract/Free Full Text]
  62. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. New Engl J Med (1996) 335:1182–1196.[Abstract/Free Full Text]
  63. Brodde O.E, Michel M.C, Zerkowski H.R. Signal transduction mechanisms controlling cardiac contractility and their alterations in chronic heart failure. Cardiovasc Res (1995) 30:570–584.[Free Full Text]
  64. Beinlich C.J, Morgan H.E. Control of growth in neonatal pig hearts. Mol Cell Biochem (1993) 119:3–9.[CrossRef][Web of Science][Medline]
  65. Knowlton K.U, Michel M.C, Itani M, et al. The alpha-1A-adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. J Biol Chem (1993) 268:15374–15380.[Abstract/Free Full Text]
  66. Milano C.A, Dolber P.C, Rockman H.A, et al. Myocardial expression of a constitutively active alpha(1B)-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc Natl Acad Sci USA (1994) 91:10109–10113.[Abstract/Free Full Text]
  67. D'Angelo D, Sakata Y, Lorenz J, et al. Transgenic G{alpha}q overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci USA (1997) 94:8121–8126.[Abstract/Free Full Text]
  68. Go L.O, Moschella M.C, Watras J, et al. Differential regulation of two types of intracellular calcium release channels during end-stage heart failure. J Clin Invest (1995) 95:888–894.[Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Stem CellsHome page
J. Satin, I. Itzhaki, S. Rapoport, E. A. Schroder, L. Izu, G. Arbel, R. Beyar, C. W. Balke, J. Schiller, and L. Gepstein
Calcium Handling in Human Embryonic Stem Cell-Derived Cardiomyocytes
Stem Cells, August 1, 2008; 26(8): 1961 - 1972.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
C. Pinet, V. Algalarrondo, S. Sablayrolles, B. Le Grand, C. Pignier, D. Cussac, M. Perez, S. N. Hatem, and A. Coulombe
Protease-Activated Receptor-1 Mediates Thrombin-Induced Persistent Sodium Current in Human Cardiomyocytes
Mol. Pharmacol., June 1, 2008; 73(6): 1622 - 1631.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
A. V. Zima, D. J. Bare, G. A. Mignery, and L. A. Blatter
IP3-dependent nuclear Ca2+ signalling in the mammalian heart
J. Physiol., October 15, 2007; 584(2): 601 - 611.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
A. V. Zima and L. A. Blatter
Inositol-1,4,5-trisphosphate-dependent Ca2+ signalling in cat atrial excitation-contraction coupling and arrhythmias
J. Physiol., March 15, 2004; 555(3): 607 - 615.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
L. A Blatter, J. Kockskamper, K. A Sheehan, A. V Zima, J. Huser, and S. L Lipsius
Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes
J. Physiol., January 1, 2003; 546(1): 19 - 31.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
L. Mackenzie, M. D Bootman, M. Laine, M. J Berridge, J. Thuring, A. Holmes, W.-H. Li, and P. Lipp
The role of inositol 1,4,5-trisphosphate receptors in Ca2+ signalling and the generation of arrhythmias in rat atrial myocytes
J. Physiol., June 1, 2002; 541(2): 395 - 409.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Woodcock, E. A
Right arrow Articles by Binah, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Woodcock, E. A
Right arrow Articles by Binah, O.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?