Download Ins(1,4,5)P and cardiac dysfunction

Cardiovascular Research 40 (1998) 251–256
Review
Ins(1,4,5)P3 and cardiac dysfunction
a,
a
b
Elizabeth A. Woodcock *, Scot J. Matkovich , Ofer Binah
a
b
Cellular Biochemistry Laboratory, Baker Medical Research Institute, Commercial Road, Prahran, Victoria, Australia
Rappaport 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
Received 18 February 1998; accepted 26 May 1998
Keywords: Arrhythmia (mechanisms); Calcium (cellular); Signal transduction; Reperfusion; Immunology
1. Introduction
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
Ca 21 -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-b (PLC-b) isoforms or
receptor tyrosine kinases and PLC-g 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 Ca 21 stores in the
*Corresponding author. Tel.: 161-3-9522-4387; Fax: 161-3-95211362; E-mail: [email protected]
endoplasmic reticulum [sarcoplasmic reticulum (SR) in
muscle cells] causing a rapid and quantal release of Ca 21
[2]. In most non-cardiac cell types, this Ins(1,4,5)P3 initiated Ca 21 response can be perpetuated by the process
of Ca 21 -induced Ca 21 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 Ca 21
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
Ca 21 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
Ca 21 channels (ICa,L ). This in turn leads to a subsequent
release of Ca 21 from the ryanodine receptor-operated
stores of the SR. The Ca 21 released from the SR binds to
troponin-C and activates the coupling of actin to myosin,
resulting in contraction of myofilaments. Removal of Ca 21
from the cytosol is accomplished by means of several
mechanisms including the sarcolemmal Na 1 –Ca 21 exchanger and the Ca 21 -ATPases of the sarcolemma and the
SR. None of these processes involve Ins(1,4,5)P3 , and
factors which activate PLC, such as a 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
Ca 21 slowly [5]. It is probably this slow release which
prevents the Ca 21 generated by Ins(1,4,5)P3 from inducing
Ca 21 -induced Ca 21 release. Instead, the Ca 21 generated
Time for primary review 33 days.
0008-6363 / 98 / $ – see front matter  1998 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 98 )00187-4
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E. A. Woodcock et al. / Cardiovascular Research 40 (1998) 251 – 256
by Ins(1,4,5) 3 has been reported to initiate slow Ca 21
oscillations [6]. Such slow increases in [Ca 21 ] 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 [Ca 21 ] 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 1 –Ca 21 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 [Ca 21 ] i can
affect myocyte function indirectly by activating a variety
of intracellular components such as Ca 21 -dependent protein kinases, phosphatases, proteases and endonucleases
[15,16]. Such actions are likely responsible for the more
chronic effects of Ca 21 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 Ca 21 or
depletion of intracellular stores. However, not all apoptotic
pathways appear to utilise intermediates which interact
with Ca 21 stores. For recent reviews on signalling pathways in apoptosis see Refs. [20–23].
2. Inflammatory heart disease
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 Ca 21 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-a
[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 [Ca 21 ] 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 [Ca 21 ] 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-g nor to interact with G proteins to activate PLC-b
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 Ca 21 overload and
apoptotic death. This scenario therefore suggests that
Ins(1,4,5)P3 generation initiates changes in Ca 21 which, in
turn, cause electrophysiological disturbances resulting in
further Ca 21 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.
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 Ca 21 in the apoptotic response, these studies identified
different mechanisms as being responsible for regulating
the Ca 21 levels. However, a number of studies have
reported a relationship between apoptosis and depletion of
intracellular Ca 21 stores without a requirement for entry of
extracellular Ca 21 [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
E. A. Woodcock et al. / Cardiovascular Research 40 (1998) 251 – 256
253
Fig. 1. Initiation of electrophysiological disturbances (DV ) 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.
type-2 receptor is most abundant in the cardiomyocytes
[35].
Not all studies have demonstrated a requirement for
rises in cytosolic Ca 21 or depletion of Ca 21 stores and
why Ca 21 should be required for apoptosis under some
conditions and not others is not clear. Some of the
enzymes involved are Ca 21 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 Ca 21
overload and thus potentiate the cell death pathway. This
possibility is illustrated by the broken arrow in Fig. 2.
3. Ischaemia and reperfusion
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
Fig. 2. Electrophysiological and apoptotic responses to elevated
Ins(1,4,5)P3 . The possibility that alterations in electrical control mechanisms enhance Ca 21 overload and thus contribute to apoptosis is indicated
by the broken arrow.
254
E. A. Woodcock et al. / Cardiovascular Research 40 (1998) 251 – 256
nervous system and there is evidence for linkage to
stimulation of a 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 a 1 -adrenergic agonists and
thrombin, only under ischaemic and reperfusion conditions, suggests some perturbation of the signalling pathways activated by a 1 -receptors and thrombin receptors in
the myocardium under these conditions.
Both a 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 a 1 -receptor or
thrombin receptor activation in hearts perfused with bloodfree 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 a 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
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.
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].
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 Ca 21 homeostasis
which are self-perpetuating and cause a worsening Ca 21
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
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 Fasexpressing 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
a 1 -adrenergic receptors but the mechanisms involved are
likely different and derive primarily from a marked
reduction in b-adrenergic activity [63] resulting in an
increase in the relative importance of a 1 -receptor-mediated
responses. The role of a 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]
E. A. Woodcock et al. / Cardiovascular Research 40 (1998) 251 – 256
and recent studies have pointed to a substantial role of G q ,
the G protein mediating a 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
There is now substantial evidence that Ins(1,4,5)P3 , by
virtue of its role in Ca 21 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.
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