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Introduction
Abnormalities of cardiac ion channels have been linked to a variety
of inherited and acquired cardiac diseases including myocardial
ischemia, hypertrophy, heart failure, and arrhythmias[1-5].
In addition, ion channels may also be mediators of the cardioprotective
effects of ischemic preconditioning (IPC)[6,7]. While
cation (K+, Na+, and Ca2+) channels
have received the most attention in the past four decades, the role
of anion channels in the cardiovascular system has been largely
ignored. Within the last 15 years, a re-surgence of interest in
Cl- channels in the cardiovascular system has led to
the discovery of at least seven different types of Cl-
currents in cardiac cells from different regions of the heart and
in different species[8]. Intensive efforts have been
given to characterize the properties of these anion channels at
the cellular and molecular levels. More details about the biophysical,
pharmacological, and molecular properties of Cl- channels
in the heart can be found in several recent excellent review articles[8-11].
It has also been demonstrated in recent studies that Cl-
channels may be involved in the regulation of a large repertoire
of cellular functions, including cellular excitability, cell volume
homeostasis, intracellular organelles acidification, cell migration,
proliferation and differentiation, and apoptosis[8,9,12].
With the recent identification of molecular entities responsible
for cardiac Cl- channels[8] and the genes
mapped to specific human chromosomal locations[13], gene
targeting and transgenic techniques have been used to delineate
the functional role of Cl- channels in the context of
health and disease. It has been reported that Cl- channels
could contribute to: 1) arrhythmogenesis in myocardial injury; 2)
the adaptive remodeling of the heart during myocardial hypertrophy
and heart failure; and 3) IPC. Therefore, anion channels represent
very attractive novel targets for therapeutic approaches to the
treatment of heart diseases. In this review, we will briefly summarize
the major findings and recent advances in the study of functional
role of anion channels in the heart.
Anion channels in the heart
Since the independent discovery of a cAMP-activated Cl-
current in the guinea pig heart by Bainski et al, Harvey
and Hume in 1989[14,15], intensive efforts have been
made to characterize Cl- channels in the cardiovascular
system at both the cellular and molecular levels. These have been
recently reviewed and thoroughly described elsewhere[8-11]
and will not be repeated in this review. Briefly, at the molecular
level, all cardiac Cl- channels described so far may
fall into the following Cl- channel gene families (Figure
1): 1) the cystic fibrosis transmembrane conductance regulator (CFTR),
which is a member of the adenosine triphosphate-binding cassette
(ABC) superfamily and may be responsible for the Cl-
currents activated by protein kinase A (PKA) (ICl.PKA)[14-16],
protein kinase C (PKC) (ICl.PKC)[17,18],
and extracellular ATP (ICl.ATP) in the heart[19-21];
2) ClC voltage-gated Cl- channel superfamily: a) ClC-2,
which is responsible for the hyperpolarization- and cell swelling-activated
inwardly rectifying Cl--current (ICl.ir)[22-24];
b) ClC-3, which is responsible for the volume regulated outwardly
rectifying Cl- current (ICl.vol), including
the basally-activated (ICl.b)[25] and
swelling-activated (ICl.swell) components[25-34];
3) CLCA-1, which was thought to be responsible for the Ca2+-activated
Cl- current (ICl.Ca)[35-38];
and 4) Bestrophin, a new candidate for ICl.Ca[39-42].
Further studies on the molecular and functional properties of these
Cl- channel genes are necessary to define the structure
of the channel proteins and to elucidate the physiological and clinical
significance of these channels.
Functional role of Cl- channels in cardiac diseases
Theoretically, Cl- channels could be involved in the
regulation of cellular excitability, cell volume homeostasis, intracellular
organelles acidification, cell proliferation and differentiation,
and apoptosis[12]. Thus, they may have important physiological
and pathological significance in cardiac function under normal and
pathological (hypoxia, ischemia, myocardial infarction, hypertrophy,
and heart failure) conditions. Mutations in several Cl-
channels have been known to result in human inherited diseases[13].
But the exact role of Cl- channels in human cardiovascular
physiology and pathophysiology is still unclear[8]. The
ability to examine the exact role of Cl- channels in
human cardiovascular physiology and pathology has been hampered
by the lack of specific pharmacological and molecular tools. With
the recent identification of the molecular entities responsible
for Cl- channels in the heart[8] and the genes
mapped to specific human chromosomal locations[13], it
is now possible to overcome these obstacles by use of gene targeting
and trans-genic animals. We have been using a multitude of approaches
from traditional methodologies including bio-physics, biochemistry,
electrophysiology, and pharmacology to state-of-the-art technologies
including telemetry system, echocardiography, genomics, and proteomics
to effectively and accurately define the role of each Cl-
channel in heart function in the context of health and disease.
Functional role in electrophysiology and arrhythmogenesis
Estimates of intracellular Cl- activity (aiCl)
in cardiac myocytes from ion-selective microelectrode studies indicate
the equilibrium potential for Cl- (ECl)
be more positive than the resting membrane potential under normal
physiological conditions with an extracellular Cl- concentration
([Cl-]o) of 145 mmol/L and an intracellular
Cl- concentration ([Cl-]i) of 10
to 20 mmol/L[43-46]. Because the ECl
is within a membrane potential range (usually -65 to -40 mV) that
can be either negative or positive to the actual membrane potential
during the normal cardiac cycle, activation of cardiac Cl-
channels can generate both inward and outward currents (Figure 2).
Thus, compared with cationic channels, Cl- channels have
the unique ability to cause both depolarization as well as repolarization
during the action potential and produce significant effects on cardiac
pacemaker activity and action potential characteristics.
The degree to which activation of Cl- currents depolarizes
the resting membrane or accelerates the repolarization of action
potential depends critically on the actual value of ECl
and the magnitude of the Cl- conductance relative to
the total membrane conductance. Under physiological conditions the
transmembrane Cl- gradient is asymmetrical. Thus, the
activation of CFTR and ClC-3 Cl- channels in the heart
will result in outwardly rectifying currents. This will have more
significant effects at positive potentials to accelerate repolarization
and shortening of the action potential duration compared with smaller
depolarizing effects at negative potentials near the resting membrane
potential (Figure 2). The ability of Cl- current activation
to depolarize cardiac cells is also opposed by the presence of a
large background K+ conductance that normally controls
the resting membrane potential. Both abbreviation of APD and depolarization
of Em upon activation of Cl- channels
may play a role in rhythm disturbance and likely contribute to arrhythmogenesis
under pathological conditions.
CFTR and arrythmogenesis CFTR channels are closed
under basal conditions but can be open under conditions where intracellular
PKA- and PKC-dependent phosphorylation activity is increased. A
major physiological role of activation of CFTR channels may be to
minimize (oppose) the significant action potential prolongation
associated with ¦Â-adrenergic stimulation of ICa.
This is expected to contribute to action potential shortening during
strong adrenergic stimulation and faster heart rates. Therefore,
activation of CFTR channels may prevent excessive prolongation of
APD and protect the heart against the development of early after
depolarizations (EAD) and triggered activity caused by activation
of Ca2+ channels in the presence of ¦Â-adrenergic stimulation.
EAD arising from phase 2 and 3 underlie focal triggered tachyarrhythmias
and repolarization abnormalities, which contribute to cardiac sudden
death[47]. It is well- established that APD prolongation
favors EAD by allowing recovery of inward currents and, conversely,
shortening of APD makes it more difficult to induce EAD. Therefore,
activation of CFTR channels should protect against focal triggered
arrhythmias. However, when background K+ conductance
is reduced in the case of myocardial hypokalemia, activation of
CFTR channels will cause significant membrane depolarization and
induce abnormal automaticity leading to the development of, EAD
(dotted red lines in Figure 2A). These predicted effects of CFTR
channel activation on APD and automaticity have been verified experimentally
by manipulations of the Cl- gradient or the use of Cl-
channel blockers[11,48-51]. Histamine was found to activate
CFTR channels in ventricular myocytes and induce oscillatory activity
and abnormal impulses in the heart, although the contribution of
CFTR channels to these arrhythmogenic activities has not been further
explored. It has been shown that activation of CFTR channels contributes
to hypoxia-induced shortening in APD[52]. Activation
of CFTR channels may accelerate the development of reentry because
of the shortening of APD and refractoriness and a decrease in conduction
velocity caused by a slight depolarization of diastolic potential
leading to Na+ channel inactivation.
ClC-3 and arrhythmogenesis The current through ClC-3 channels
under basal or isotonic conditions is small, but can be further
activated by stretching of the cell membrane by inflation and/or
cell swelling induced by exposure to hypoosmotic solutions. Activation
of ClC-3 channels is expected to induce a similar effect on cardiac
action potentials as that of activation of CFTR channels (Figure
2A) because both Cl- currents through both channels are
relatively time- and voltage-independent over the physiological
range of membrane potentials[53,54]. Activation of ClC-3
channels might produce more significant action potential shortening
than CFTR channels because of its stronger outwardly rectifying
property. Because myocardial cells swell during hypoxia and ischemia,
and the washout of hyperosmotic extracellular fluid after reperfusion
induces further cell swelling, activation of ClC-3 channels may
also contribute to hypoxia, ischemia and reperfusion induced shortening
in APD and arrhythmias[9,53,54]. Abbreviation of APD
and, therefore, the effective refractory period reduces the length
of the conducting pathway needed to sustain reentry (wavelength).
In principle, this favors the development of atrial or ventricular
fibrillation, which depends on the presence of multiple reentrant
circuits or rotating spiral waves. ICl.swell also
may slow or enhance the conduction of early extrasystoles, depending
on the timing. In the case of myocardial hypertrophy and heart failure,
ionic remodeling is one of the major features of pathophysiological
changes[55]. It has been found that the current densities
and molecular expression of several major repolarizing K+
channels (such as Kv4x) are significantly reduced, which may be
responsible for the prolongation of APD and development of EAD[55].
However, under these conditions, ICl.vol is constitutively
active[56]. The persistent activation of ICl.vol
may limit the APD prolongation and make it more difficult to elicit
EAD. Indeed, as shown in Figure 3, in myocytes from hearts in failure,
block of ICl.vol by tamoxifen significantly prolonged
APD and decreased the depolarizing current required to elicit EAD
by about 50% (Figure 4B) and hyperosmotic cell shrinkage, which
also inhibits ICl.vol, was almost equivalent to
tamoxifen in causing EAD in these myocytes (Figure 4C)[9].
Therefore, the consequences of activation of ICl.vol
are very complex. It may be detrimental, beneficial, or simultaneously
both in different parts of the heart.
It has been shown that mechanical stretching or dilation of the
atrial myocardium is able to cause arrhythmias. Since ICl.swell
was also found in sino-atrial (S-A) nodal cells, ClC-3 channels
may serve as a mediator of mechanotransduction and play a significant
role in the pacemaker function if they act as the stretch activated
channels in these cells[9,57]. Baumgarten's laboratory
has recently demonstrated that ICl.swell in ventricular
myocytes could be directly activated by mechanical stretch through
selectively stretching ¦Â1-integrins with mAb-coated magnetic bEAD[9,58,59].
Although it has been suggested that stretch and swelling activate
the same anion channel in some non-cardiac cells, further study
is needed to determine whether this is true in cardiac myocytes.
Ca2+-activated Cl- channel and arrhythmogenesis As
illustrated in Figure 2B, the activation of ICl.Ca
will have considerably different effects on cardiac action potentials
and resting membrane potential from those of CFTR and ClC-3 channels,
even though ICl.Ca is also expected to be outwardly
rectifying under physiological conditions. This is because the kinetic
behavior of ICl.Ca is significantly determined
by the time course of the [Ca2+]i transient[60].
Normally, ICl.Ca will have insignificant effects
on the diastolic membrane potential, as resting [Ca2+]i
is low. When [Ca2+]i is substantially increased
above the physiological resting level, however, ICl.Ca
carries a significant amount of transient outward current.
ICl.Ca will be activated early during the action
potential in response to an increase in [Ca2+]i
associated with Ca2+-induced Ca2+ release
(CICR). The time course of decline of the [Ca2+]i
transient will determine the extent to which ICl.Ca
contributes to early repolarization during phase 1 (Figure 2B).
In the rabbit left ventricle, ICl.Ca contributes
to APD shortening in subendocardial myocytes but not in subepicardial
myocytes. These differences in functional expression of ICl.Ca
may reduce the electrical heterogeneity in the left ventricle[61].
In Ca2+-overloaded cardiac preparations, ICl.Ca
can contribute to the arrhythmogenic transient inward current
(ITI, Figure 2B)[62]. ITI
produces delayed after-depolarization (DAD)[63] and induces
triggered activity (red dotted line in Figure 2B), which is an important
mechanism for abnormal impulse formation. In sheep Purkinje and
ventricular myocytes, activation of ICl.Ca was
found to induce DAD and plateau transient repolarization (Figure
4)[64]. Therefore, blockade of ICl.Ca may
be potentially antiarrhythmogenic by reducing DAD amplitude and
triggered activity based on DAD. However, the role of ICl.Ca
in phase 1 repolarization and the generation of EAD and DAD of either
normal or failing human heart seem very limited[65-67].
Therefore, the clinical relevance of ICl.Ca blockers
remains to be determined.
ClC-2 and arrhythmogenesis ClC-2 channels are
activated by hyperpolarization, cell swelling, and acidosis and
have an inwardly rectifying I-V relationship. During
the cardiac action potential, therefore, the ClC-2 channel will
conduct a mainly inward current as a result of Cl- efflux
at negative membrane potentials and cause a depolarization of the
resting membrane potential of cardiac cells. At membrane potentials
more positive than ECl, ClC-2 may conduct a small
outward current as a result of Cl- influx and may accelerate
repolarization of the action potential. It is also possible that,
in a manner analogous to the role and tissue distribution pattern
of the cationic pacemaker channels (If), Cl.ir
channels normally play a much more prominent role in the SA or AV
nodal regions of the heart (Figure 2C). The hyperpolarization-activated
inward rectifying Cl- current (ICl.ir)
through ClC-2 channels under basal or isotonic conditions is small,
but can be further activated by hypotonic cell swelling[22]
and acidosis[23,24]. The volume-sensitivity of the channel
also suggests its role in cell volume regulation. The sensitivity
of ClC-2 to [H+]o and cell volume may be of
pathological importance during hypoxia- or ischemia-induced acidosis
or cell swelling. Therefore, it may be possible that the significance
of ICl.ir in the heart becomes more prominent
under some pathological conditions (ischemia or hypo- xia)[68].
As a matter of fact, ischemia and acidosis have consistently been
shown to depolarize the resting membrane potential of cardiac myocytes,
increase automaticity and cause lethal arrhythmias, although the
mechanism has remained obscure[1,11]. It is reasonable
to suggest that an increase in ClC-2 conductance could be responsible
for these phenomena and be pro-arrhythmic. Drugs targeting ClC-2
channels could be anti-arrhythmic. Therefore, the ClC-2 channels
could have important clinical significance for such cardiac diseases
as arrhythmias, ischemia and reperfusion, and congestive heart failure.
Activation of ClC-2 current should mainly cause a depolarization
of the RMP and it is suggested that the acidosis-induced increase
in ICl,ir might underlay the depolarization of
the resting membrane potential during acidosis or hypoxia[23,24].
It should be pointed out that prediction of the consequences of
activation of Cl- channels is complex. Most studies that
have examined the contribution of Cl- currents to the
cardiac action potential and arrhythmias have relied on anion antagonist
and substitution experiments. The pharmacological specificity of
many of these anion channel antagonists can be problematic, and
anion substitution, in addition to altering anion movement through
channels, can have other unpredictable side effects on other transport
proteins and signaling pathways[69,70]. With the recent
identification of the molecular entities responsible for Cl-
channels in the heart, it is now possible to combine electrophysiological,
molecular biological, and especially gene-targeting techniques in
the study of cardiac Cl- channels to effectively and
accurately define the role of each Cl- channel in heart
function. However, as the distribution of various Cl-
channels in the heart varies among cell types and regions[8],
activation of these channels may increase the dispersion of the
electrophysiological properties and provide substrates for heart
diseases involving cardiac arrhythmias and myocardial remodeling.
Functional role of Cl- channels in cardiac IPC
Ischemia causes myocardial damage and leads to infarction through
apoptosis (programmed cell death) and necrosis. IPC is a phenomenon
in which brief ischemic episodes elicit protection of the heart
against sustained ischemia. It has been suggested that both sarcolemmal
and mitochondrial ATP-sensitive potassium channels (sarc-KATP
and mito-KATP, respectively) may serve as triggers or
end-effectors. PKC may link cellular signal events during ischemia
to the activation of end-effectors, which will somehow prevent or
delay apoptosis and protect the cardiac myocytes. The precise mechanism
of IPC, however, remains to be elucidated. Several recent studies
have pointed to a potential role of Cl- channels in IPC.
ICl.swell and ClC-3 in IPC It
has been reported that the block of ICl.swell
in rabbit cardiac myocytes inhibits preconditioning by brief ischemia,
hypoosmotic stress[71,72] and adenosine receptor agonists[73].
These studies are solely based on the use of several Cl-
channel blockers, such as anthracene-9-carboxylic acid (9-AC) and
4-acetamide-4'-isothiocyanato-stilbene-2,2'-disulfonic acid (SITS).
As mentioned above, these pharmacological tools lack specificity
to a particular Cl- channel in the heart and may also
act on other ion channels or transporters. Therefore it has been
very difficult to confirm the causal role of ICl.swell
in IPC[74]. The exact role of ICl.swell
in IPC needs to be further determined adequately using more specific
approaches. To specifically test whether the volume-regulated Cl-
channels are indeed involved in IPC, we have recently established
in vitro and in vivo IPC models in ClC-3 knockout
mice (ClCn3-/-). Our preliminary results indicate that
targeted inactivation of ClC-3 gene prevented protective
effects of late IPC but not of early IPC, suggesting that ICl.swell
may contribute differently to early and late IPC[75].
The underlying mechanisms for these differential effects are currently
unknown. Recent reports, however, suggest that ICl.swell
and ClC-3 might play an important role in apoptosis. Cl-
channel blockers 4,4'-diisothio-cyano-stilbene-2,2'-disulphonate
(DIDS) and 5-nitro-2-(3-phenylpropyllamino)-benzoic acid (NPPB)
were as potent as a broad-spectrum caspase inhibitor in preventing
apoptosis and elevation of caspase-3 activity and improved cardiac
contractile function after ischemia and in vivo reperfusion[76].
Transgenic mice overexpressing Bcl-2 in the heart had significantly
smaller infarct size and reduced apoptosis of myocytes after ischemia
and reperfusion[77]. It has been shown that Bcl-2 induces
up-regulation of ICl.vol by enhancing ClC-3 expression
in human prostate cancer epithelial cells[78]. Cell shrinkage
is an integral part of apoptosis, suggesting that ICl.vol
and ClC-3 might be intimately linked to apoptotic events through
regulation of cell volume homeostasis[78,79].
CFTR channels and IPC Several lines of evidence
suggest that CFTR channels could be involved in IPC including: (1)
sarc-KATP blockers, such as glibenclamide, which suppress
IPC protection, also block CFTR channels in noncardiac[80,81]
and cardiac cells[19,82]; (2) PKC and PKA, two essential
second messengers in IPC[83,84] can activate CFTR channels[8,19,85];
and (3) triggers of IPC (nitric oxide, opioids, and adenosine etc)
can all regulate CFTR channel function[8]. We have directly
tested whether activation of CFTR channels is involved in IPC by
studying hemodynamics and tissue injury of hearts isolated from
WT and two strains of CFTR knockout (CFTR-/-)
mice subjected to ischemia and reperfusion. In isolated mouse heart
perfused in the Langendorff or working heart mode, we have recently
found that targeted inactivation of CFTR gene prevented protection
on cardiac function and myocardium injury against sustained ischemia
by ischemic preconditioning (Figure 5)[86]. Our in
vivo studies using both wild type and CFTR knockout mice
also demonstrated that CFTR was an important mediator in both early
and late ischemic preconditioning in the heart[87]. Several
mechanisms may be responsible for a functional role of CFTR channels
in mouse heart IPC: (1) It has been demonstrated that cardiac CFTR
plays a role in early action potential shortening during hypoxia
and ischemia[52]. Activation of CFTR will also decrease
resting membrane potential and action potential duration, thereby
limiting intracellular Ca2+ overload and cell damage[8];
(2) The CFTR channel is an important transporter of sphingosine
1-phosphate (S-1-P)[88], which has recently emerged as
an important lipid messenger involved in IPC[89]; (3)
CFTR is permeable not only to Cl-, but also to larger
organic ions, as well as reduced and oxidized forms of glutathione
(GSH)[90]. Therefore CFTR may contribute to the control
of oxygen stress-induced apoptosis and the regulation of inflammation
and the immune responses; (4) CFTR might decrease intracellular
pH and modulate apoptosis[91]; (5) CFTR functions as
a regulator of volume-dependent homeostatic cell mechanisms in cell
proliferation and apoptosis[92]. We are currently in
the process of investigating these potential mechanisms and the
relative role of CFTR in early and late preconditioning.
ICl.Ca in IPC It has been well
known that ischemia/reperfusion usually causes a cytosolic overload
of Ca2+ in cardiac myocytes[93,94]. Therefore,
it is very possible that ICl.Ca may be activated
during ischemia and reperfusion[38,62,64,95-98]. But,
no information for the possible involvement of ICl.Ca
in IPC is currently available.
Functional role of Cl- channels in myocardial hypertrophy
and heart failure Myocardial hypertrophy and its progression
to dilated cardiomyopathy or heart failure are characterized by
not only structural remodeling, including hypertrophic growth of
cardiac myocytes (changes in cell volume) and changes in the cytoskeleton
and extracellular matrix (ECM)[99,100] but also ionic
remodeling, that is, changes in expression and activity of many
ion channels. It should be pointed out that ionic remodeling during
the progression of hypertrophy to heart failure provides not only
substrates for arrhythmias but also cellular mechanisms for structural
remodeling. During the remodeling process, multiple neurohormonal
and intracellular signaling cascades, including tyrosine kinases,
PKA, PKC, protein phosphatases, MAP kinases, and endothelin, are
activated[101]. These second messengers are well-known
effective regulators of various ion channels. Indeed, it has been
found that several cation channels, such as K+ channels,
Ca2+ channels, and stretch-activated non-selective channels,
undergo significant changes. Recent evidence also supports possible
involvement of anion channels in the remodeling process.
ICl.swell and ClC-3 in myocardial hypertrophy
and heart failure ICl.swell is
persistently activated in ventricular myocytes from a canine pacing-induced
dilated cardiomyopathy model[102]. Using the perforated
patch-clamp technique, Clemo et al found that, even in isotonic
solutions, a large 9-AC-sensitive, outwardly rectifying Cl-
current was recorded in heart failure myocytes but not in normal
myocytes. Graded hypotonic cell swelling (90%-60% hypotonic) failed
to activate additional current while graded hypertonic cell shrinkage
caused an inhibition of the "basal" Cl- current
in failure myocytes. Moreover, the maximum current density of the
ICl.swell in failure myocytes was about 40% greater
than that in osmotically swollen normal myocytes. Constitutive activation
of ICl.swell is also observed in several other
animal models of heart failure, such as a rabbit aortic regurgitation
model of dilated cardiomyopathy[103,104] and a dog model
of heart failure caused by myocardial infarction[105].
In human atrial myocytes obtained from patients with right atrial
enlargement and/or elevated left ventricular end-diastolic pressure,
a tamoxifen sensitive ICl.swell was also found
to be persistently activated[106]. It is not known at
this time whether ICl.swell is also persistently
activated in hypertrophied non-failure (or non-dilated) myocytes
in the above described models or in the human heart. In a rat aortic
constriction model, however, a 9-AC-sensitive Cl- current
is present in hypertrophied ventricular myocytes but not in control
myocytes, and this hypertrophy-activated Cl- current
seems to contribute to the shortening of APD in the hypertrophied
cells[107]. It is not known, however, whether this hypertrophy-activated
Cl- current is the same as ICl.swell
because the volume-sensitivity of this Cl- current was
not assessed. Nevertheless, it is possible that persistent activation
of ICl.swell is a common response of cardiac myocytes
to hypertrophy or heart failure-induced remodeling. The mechanism
for this phenomenon is still not clear. Perhaps the cell volume
increase caused by hypertrophy and cell membrane stretch caused
by dilation, are both involved in the activation of ICl.swell.
Alternatively, the persistent activation of ICl.swell
may be caused by signaling cascades activated during hypertrophy
and heart failure independent of changes in cell length and volume,
or both. ICl,swell could be activated by direct
stretching of b1-integrin through focal adhesion kinase (FAK) and/or
Src[58]. Mechanical stretch of myocytes also releases
angiotensin II (AngII), which binds to AT1 receptors (AT1R) and
stimulates FAK and Src in an autocrine-paracrine loop. A recent
study by Browe and Baumgarten suggests that the stretch of b1-integrin
in cardiac myocytes activates ICl.swell by activating
AT1R and NADPH oxidase and, thereby, producing reactive oxygen species.
In addition, NADPH oxidase may be intimately coupled to the channel
responsible for ICl.swell, providing a second
regulatory pathway for this channel through membrane stretch or
oxidative stress[59]. This finding is very important
for further understanding of the mechanism for hypertrophy activation
of ICl.swell and ClC-3 channels and their relationship
to hypertrophy and heart failure as it is very well known that Ang
II plays a crucial role in myocardial hypertrophy and heart failure[108].
The functional and clinical significance of ICl.swell
in the hypertrophied and dilated heart is currently unknown.
Using a mouse aortic banding model of myocardial hypertrophy, we
have recently found that targeted disruption of ClC-3 gene (ClCn3-/-)
accelerated the development of myocardial hypertrophy and the discompensatory
process[109], suggesting that activation of ICl.vol
might be important in the adaptive remodeling of the heart
during pressure overload. Further studies on the mechanism for the
ClC-3 channels' effects on hypertrophy and heart failure are in
progress in our laboratory. It is well accepted that in most cells
activation of ICl.vol represents one important
trigger to initiate regulatory volume decrease (RVD) when cells
swell[12]. Cell volume homeostasis, therefore, could
be an important function of ICl.swell activation
in the heart. Activation of Cl- conductance causes significant
changes in APD and intracellular Ca2+ concentration,
and should also affect excitation-contraction (E-C) coupling, contractility,
and other hemodynamic functions of the heart[8,11]. Recent
studies suggest that ICl.swell and ClC-3 channels
play important roles in cell prolifera-tion[110], differentiation[111],
migration[112], and apoptosis[78,79]. All
of these have been demonstrated as important cellular processes
in myocardial remodeling during hypertrophy and heart failure[113].
CFTR in myocardial hypertrophy and heart failure Remodeling
of CFTR channels has been observed in myocardial hypertrophy and
heart failure. Using in situ mRNA hybridization in a combined
pressure and volume overload model of heart failure in the rabbit,
Wong et al found that the normal epicardial to endocardial
gradient of CFTR mRNA expression is reversed due to a significant
decrease in epicardial expression of CFTR mRNA in the rabbit left
ventricle[114]. A post-translational change in the CFTR
expression could be responsible for this phenomenon[115].
The loss of the normal transmural gradient of repolarising ion channels
is likely to contribute to instability of repolarisation in the
hypertrophied heart and hence increased risk of cardiac arrhythmias
in patients with heart failure. The exact functional and clinical
significance of the changes in CFTR expression during hypertrophy
and heart failure is currently not clear and merits further study.
ICl.Ca in myocardial hypertrophy and heart
failure The critical role of Ca2+ in cardiac
development, function, and disease is undisputable. Despite the
heterogeneous etiology and overt manifestations of heart failure,
abnormalities in Ca2+ handling are prominent, and alterations
in Ca2+ homeostasis are a hallmark of myocardial hypertrophy
and heart failure[116]. Ca2+ transients in
failing cardiac myocytes, for example, are characterized by diminished
amplitude, elevated diastolic Ca2+ levels, and prolonged
decay of the Ca2+ transients. In non-cardiac cells, ICl.Ca
could be an important mediator of apoptosis[117]. But,
information on the possible involvement of ICl.Ca
in heart failure is currently very limited. It is reported that
ICl.Camay play little, if any, role in the electrical
remodeling of human end-stage failing heart[66,67,118].
Conclusions and future directions
Although the field of anion channels in cardiac physiology and
pathophysiology lags significantly behind that of cation channels,
the gap can now be narrowed with the recent identification of molecular
entities responsible for cardiac Cl- channels[8],
their genes mapped to specific human chromosomal locations[13]
and the use of gene targeting and transgenic animals. Recent efforts
not only at the cellular and molecular levels but also the isolated
organ and whole animal levels have provided strong evidence that
Cl- channels may play an important role in cardiac diseases,
including arrhythmias, myocardial ischemia, hypertrophy, and congestive
heart failure. Anion channels in the heart, therefore, may represent
important novel targets for therapeutic agents against heart diseases.
Despite these exciting developments, further investigations of
the cellular and molecular mechanisms by which the Cl-
channel proteins function to impart a physiological or a pathophysiological
phenotype may require a multitude of approaches for the assessment
of the Cl- channel functions in healthy and diseased
hearts. Although global knockout mice are invaluable experimental
models and functional genomics remains a powerful approach to understanding
the function of cardiac Cl- channels, several theoretical
and practical problems should be considered. First, homologous recombination
gene targeting is based on the assumption that targeting will result
in specific loss of the gene's product and will not directly affect
the expression of other genes. In reality, however, even though
the loss of the gene's product can be verified, the upregulation
of another gene in the vicinity of the targeting can occur[119]
and may readily escape detection. Such upregulation could have an
important effect on the observed phenotype. Second, a knockout may
not always be a knockout[120] such as when the targeted
gene is widely or ubiquitously expressed, when alternative splicing
variants of the gene exist[121], and when functional
channels are actually heteromultimeric and the structure might be
associated with modulatory subunits, such as Barttin for ClC channels[122].
Accessory proteins may be involved in the determination of the stability
of the channel complex in the membrane and in the modulation of
biophysical, pharmaco-logical, and regulatory properties of the
channel. Recent evidence suggests that Cl- channels,
like cation channels[52,123,124], may function as a multiprotein
complex or functional module. A functional anion channel module
may be a complex composed of the following: (a) pore forming subunit
for ion transportation; (b) auxiliary subunits for modulating pore
gating; and (c) proteins as second messengers tightly coupled to
channel function. These proteins might be intimately linked to certain
physiological functions and belong to the same subproteome. Manipulation
of one gene in the subproteome may cause changes in other proteins
of the same subproteome. Therefore, the functional consequences
of disrupting the specific gene are very difficult to predict unless
the changes in the entire subproteome are examined. Similar phenotypes
can be attained from alternative protein pathways within cellular
networks, which are influenced by disease, environmental, internal,
and biochemical stimuli. Therefore, caution should be taken when
conventional global gene knockout animals are used in functional
studies. Alternatively, tissue-specific conditional or inducible
knockout or knockin animal models may be more valuable in the phenotypic
studies of specific genes by limiting the effect of upregulation
or developmental compensation on the phenotype of manipulated genes.
Many phenotypic changes may actually be a result of posttranslational
changes caused by protein modifications such as phosphorylation
or dephosphorylation. Therefore, it is clear that conventional functional
genomics may provide only limited information on the functional
module of multiprotein complexes. We are now facing the challenge
of a major paradigm shift in the study of integrated anion channel
functions. In the postgenomic era, the recent advances in the genome
resources including genome-wide microarray profiling together with
advancement in the application of functional proteomics and bioinformatics
will certainly facilitate our understanding of the functions of
anion channels in the cardiovascular system. It is feasible that
anion channels may become novel targets for therapeutic approaches
to the treatment of cardiovascular diseases.
Acknowledgements
The research in the Laboratory of Functional Genomics and Proteomics,
Center of Biomedical Research Excellence and the Department of Pharmacology,
University of Nevada, School of Medicine is supported by grants
from the National Institutes of Health (R01-HL63914), National Center
of Research Resources (NCRR, P20RR15581).
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