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Introduction
RhoA, along with RhoB, RhoC, Rac1, Rac2, Cdc42, RhoG, and TC10,
belongs to the Ras family of small GTP-binding proteins. RhoA and
Rho-kinase (ROCK), a downstream target protein of small
GTP-binding protein Rho, are known to regulate a wide variety of
cellular processes such as changes in cell morphology, cell motility,
focal adhesions, light chain phosphorylation, and cytokinesis[1,2].
Inhibition of the RhoA/ROCK cascade has been demonstrated to elicit
beneficial effects on function of both heart tissues and vasculature.
RhoA is believed to play a key role in cell growth, myofibrillar
assembly, cardiac hypertrophy, hypertension, vascular smooth muscle
cell proliferation and migration in response to heterotrimeric G
protein receptor stimulation and to mechanical strain or tyrosine
kinase growth factors[3-8]. ROCK has been implicated
to mediate the angiotensin II (Ang II)-induced hypertrophic responses
of vascular smooth muscle cells and hypertensive vascular diseases
in hypertension[9,10]. In addition to cardiovascular
diseases, RhoA and ROCK also participate in normal physiological
processes such as pregnancy and early heart development. The mRNA
expression of RhoA and two types of ROCK (α and β) was found to
be elevated in the pregnant myometrium[11], which may
be responsible for the augmented myometrial contractility during
pregnancy. Using the small interfering RNAs (siRNA) technique, it
was reported that disruption of RhoA expression resulted in absence
of heart tube fusion and abnormal head development in chick embryos,
indicating the importance of RhoA for normal embryogenesis and early
heart development[12]. Recent studies have indicated
that inhibition of the RhoA-ROCK signal pathway may be a potential
target for a number of cardiovascular diseases including hypertension,
atherosclerosis, diabetes and hypertrophic heart failure[13].
This review will summarize the role of RhoA and ROCK in heart morphology
and function, with a special focus on the pathogenesis of heart
diseases associated with abnormal RhoA and ROCK signaling. As certain
factors such as peripheral vascular resistance may affect cardiac
afterload and subsequently cardiac contractile function, the effect
of RhoA-ROCK on cardiac morphology and function appears to be more
complex than originally thought and requires more intensive research.
Role of RhoA in cardiac hypertrophy Cardiac hypertrophy
is a cardiac physiological adaptation in response to pressure or
volume overload. However, after a prolonged period of time, this
initial adaptive response becomes maladaptive, thus switching the
heart from a compensated to a decompensated state and ultimately
increased cardiac mortality and morbidity. The Gq-RhoA-ROCK pathway,
which may be activated by several neurohormonal factors such as
angiotensin II, is believed to function as an important signaling
pathway for cardiac hypertrophy or transition from left ventricular
hypertrophy to heart failure. Activation of RhoA is essential for
sensing externally applied force, subsequently relaying onto the
actin cytoskeleton leading to translocation of extracellular signal-regulated
kinase (ERK) en route to cardiac hypertrophy[14,15].
It is believed that hypertrophy-related gene expression in response
to RhoA activation is mediated through cross-talk with β1
integrin signal pathway via an organized actin cytoskeleton[14,15].
In addition, transcription factor GATA-4, a key regulator of cardiac
genes, may also be a nuclear mediator of RhoA participating in sarcomere
assembly in cardiomyocytes. Both RhoA and GATA-4 are necessary for
sarcomeric reorganization in response to hypertrophic stimuli. It
has been demonstrated that over-expression of either protein alone
is sufficient to trigger sarcomeric reorganization[16].
In a recent study of heart failure model in Dahl salt-sensitive
rats fed an 8% NaCl diet from 8 weeks with or without the ROCK inhibitor
Y-27632, Satoh and colleagues reported elevated left ventricular
mass, cardiac myocyte cross-sectional area, interstitial fibrosis,
and contractile dysfunction shown as reduced left ventricular ejection
fraction and fractional shortening, as well as prolongation in contraction/relaxation
duration associated with increased protein expression of Galphaq
and ROCK in the Dahl salt-sensitive, salt intake Y-27632-untreated
group. Interestingly, the degree of myocardial hypertrophy was significantly
reduced in conjunction with improved contractile function but no
change in interstitial fibrosis following Y-27632 treatment in Dahl
salt-sensitive, salt intake rats[17]. These results suggest
the possibility that the Gq-ROCK signal pathway plays an important
role in the process of hypertension-induced left ventricular hypertrophy
leading to contractile dysfunction. The notion of a key role for
RhoA-ROCK in cardiac hypertrophy received convincing support from
transgenic studies using mice overexpressing RhoA or a constitutively-activated
RhoA mutant in atria and ventricles[18]. Heterozygotes
displayed high premature mortality, ventricular dilatation (without
change in mass) and dysfunction, changes in expression
of hypertrophic index gene, increases in atrial mass,
marked conduction abnormalities, and other signs of heart
failure[18]. Nevertheless, the phenotype of cardiac anomalies
in these transgenic mice is different from those commonly seen in
compensated hypertrophy, thus precluding any firm conclusion to
be drawn regarding the role of RhoA in cardiac hypertrophy. The
possible role of RhoA in cardiac hypertrophy also received indirect
evidence from the work related to 3-hydroxyl-3-methylglutaryl coenzyme
A (HMG-CoA) reductase inhibitors, or statins. Statins have been
shown to inhibit cardiac hypertrophy by cholesterol-independent
mechanisms including inhibition of activation of RhoA and Rac1[19].
Since Rac1 is a crucial component of reduced nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase, which is a main source for
reactive oxygen species (ROS) in the hearts, the fact that statins
inhibit Rac1-mediated oxidative stress may contribute to their inhibitory
effects on cardiac hypertrophy[19].
RhoA and cardiac electromechanical function Although there
have been some indications that inhibition of RhoA-ROCK may benefit
cardiac dysfunction under conditions such as heart failure or ischemia-reperfusion
cardiac injury[20], the precise role of RhoA-ROCK on
cardiac contractile function remains unclear. Using the Dahl salt-sensitive
heart failure model, it was demonstrated that inhibition of ROCK
with Y-27632 significantly improved cardiac contractile dysfunction
in Dahl salt-sensitive high salt intake heart failure model including
reconciling reduced in left ventricular ejection fraction and fractional
shortening, prolonged duration of contraction and relaxation, associated
with lessened cardiac hypertrophy. These authors also found that
the upre-gulated proto-oncogene c-fos gene expression, but
not that of ERK and p70S6 kinase phosphorylation, under heart failure
rats was decreased by inhibiting ROCK, suggesting a differential
activation of the Rho-ROCK and the ERK-p70S6 kinase pathways in
the failing hearts of Dahl salt-sensitive hypertensive rats[20].
The observation that ROCK inhibition rescues cardiac contractile
defects (reduced contractility and prolonged duration of contraction/relaxation)
is supported by cardiac function assessment obtained from the RhoA
transgenic mice. Cardiac-specific overexpression of RhoA triggered
prolongation of action potential duration and reduction in ventricular
contractility[18]. In a separate study, cardiac-specific
inhibition of ROCK was achieved by expressing Rho GDIα, an
endogenous specific GDP dissociation inhibitor for Rho family proteins,
using the a-myosin heavy chain (α-MHC) promoter. Increased
expression of Rho GDIa preserved the left ventricular systolic and
diastolic function both before and after the development of cardiac
hypertrophy, indicating that Rho GTPases may not be required for
maintenance of ventricular contractile function under basal physiological
conditions[21]. The RhoA-ROCK also participates in the
function of cardiac conducting system. Electrocardiography and intracardiac
electrophysiological evidence suggest first- and second-degree atrioventricular
(AV) block in cardiac-specific Rho GDIα (which inhibits Rho
GTPase) transgenic hearts at 1 and 4 weeks of age, respectively,
prior to the development of cardiac hypertrophy[21].
These results suggest that the RhoA-ROCK signal cascade is necessary
for cardiac electrical conduction under normal physiological conditions.
Further examination revealed that expression of connexin 40 was
significantly decreased from 1 to 4 weeks of age in the Rho GDIα
transgenic heart, which may contribute, at least in part, to the
conduction defects in the Rho GDIα transgenic mice[21].
RhoA, hypertension, and cardiac afterload Regulation of
vascular smooth muscle cell contractile state is critical for the
maintenance of vascular tone. The RhoA-ROCK signal cascade may affect
heart function indirectly through regulation of peripheral vascular
resistance. The RhoA-ROCK pathway has been demonstrated to play
an important role in a wide variety of cell functions in the vasculature
including actin cytoskeleton organization and vascular smooth muscle
contraction. The RhoA-ROCK pathway is constitutively active in a
number of organs including vascular smooth muscle under physiological
and pathophysiological conditions[22]. It is believed
that upregulated RhoA-ROCK signal cascade promotes cytosolic Ca2+
sensitization and vascular tension in smooth muscles, leading to
enhanced peripheral vascular resistance, vascular tone and subsequently
hypertension[22,23]. Myosin phosphatase is the key enzyme
responsible for myosin light chain (MLC) dephosphorylation that
regulates smooth muscle cell contraction. Vasoconstrictors and vasodilators
are expected to inhibit or promote the activity of myosin phosphatase,
respectively. It was indicated that G-protein-coupled receptor agonists
might inhibit the activity of myosin phosphatase leading to vasoconstriction
through activation of RhoA-ROCK. However, nitric oxide (NO) may
activate myosin phosphatase, leading to vasorelaxation through cGMP-dependent
protein kinase. It has been postulated that RhoA regulates vascular
smooth muscle contraction through interaction with myosin phosphatase-Rho
interacting protein, a likely new member of the myosin phosphatase
controlling myosin light chain dephosphorylation[24].
In addition to the peripheral effect, blockade of the RhoA-ROCK
signal pathway in nucleus tractus solitarii (NTS) of brain stem
decreased blood pressure, heart rate, and renal sympathetic nerve
activity in both Wistar-Kyoto (WKY) rats and spontaneously hypertensive
rats (SHR), suggesting a role of the RhoA-ROCK signal cascade in
central regulation of blood pressure[7]. Interestingly,
the magnitude of blood pressure, heart rate, and renal sympathetic
nerve activity drop was much greater in SHR than in WKY rats. Furthermore,
membrane RhoA expression and ROCK activity in NTS were enhanced
in SHR compared with WKY rats, confirming the contribution of the
NTS RhoA-ROCK pathway to blood pressure regulation via sympathetic
nervous system[7]. Additional work from the same group
suggested that activation of the RhoA-ROCK signal pathway might
contribute to neurogenic hypertensive mechanisms caused by chronic
inhibition of NO synthesis[8]. Chronic inhibition of
NO synthesis by the NO synthase (NOS) inhibitor Nù-nitro-L-arginine
methyl ester (L-NAME) is known to trigger the onset of hypertension,
which was alleviated by the ROCK inhibitor, Y-27632. Expression
of membranous RhoA and phosphorylation of the target proteins of
ROCK, the ERM (ezrin, radixin, moesin) family members, was significantly
greater in the L-NAME-treated group than control group, indicating
that activation of the RhoA-ROCK signal pathway contributes to neurogenic
hypertension triggered by chronic NOS inhibition[8].
RhoA and diabetic cardiovascular complications Prolonged
contraction and relaxation are hallmarks of diabetic cardiomyopathy,
one of the most devastating complications in diabetes[25,26].
Studies from our laboratory depicted prolonged duration of contraction
and relaxation associated with normal contractility and maximal
rate of contraction and relaxation in diabetes[25-27].
Although several mechanisms have been postulated for the diabetes-related
mechanical defects such as diabetes-induced myosin isozyme switch
(from the fast type V1 to the slow type V3),
impaired function of sarco(endo) plasmic reticulum Ca2+-ATPase
(SERCA) and Na+/Ca2+ exchanger, as well as
reduced myofilament Ca2+ sensitivity [26,28-30],
the signaling mechanisms responsible for these cellular alterations
remain poorly defined. Recently, we reported up-regulation of cardiac
RhoA signaling in diabetic hearts[27]. RhoA expression
has been demonstrated to be up-regulated in arteries from aged,
hypertensive, or diabetic rats[27,31-33]. The dynamics
of RhoA gene expression is sparsely documented although binding
of transcription factor cAMP-responsive element binding (CREB) protein/
activating transcription factor-1 (ATF-1) has been shown to increase
the RhoA promoter activity[34]. Hyperglycemia and reactive
oxygen species, which often accompany hyper-glycemia, have been
shown to increase nuclear CREB activity through a p38 MAP kinase-dependent
pathway[35,36]. Elevated oxidative stress in diabetic
heart and enhanced p38 MAP kinase activation were observed in a
preliminary study (Ren and colleagues, unpublished data), which
may be related to enhanced expression of RhoA and activity of ROCK.
Although there is little evidence depicting a direct regulation
of RhoA signaling in cardiac excitation-contraction coupling, activation
of ROCK, the Rho-dependent serine-threonine kinase, has been shown
to regulate cardiac contractility and gene expression, probably
mediated through the MAP kinase super-family[6,18,20].
One of the likely scenarios that RhoA may participate cardiac excitation-contraction
coupling is speculated to be mediated through regulation of K+
channel and action potential duration. Cardiac-specific overexpression
of RhoA was reported to prolong action potential duration and to
diminish ventricular contractility[18]. The RhoA-induced
prolongation of action potential may be related to its ability to
interrupt certain voltage-dependent K+ channel(s)[37].
These speculations are supported by our recent observation of concurrent
up-regulation of RhoA mRNA/protein and diminished Kv1.2 protein
expression in diabetic hearts (Ren and colleagues, unpublished data).
Depressed expression and function of voltage-dependent K+
channels have also been implicated in prolonged phase 3 of action
potential repolarization and thus lengthened relaxation duration
in diabetic hearts[38]. The involvement of RhoA signaling
in diabetic heart dysfunction was supported by our finding using
the ROCK inhibitor Y27632. Incubation of Y-27632 with high extracellular
glucose (25.5 mmol/L) for 12 h significantly reduced the compromised
cardiac mechanical function elicited by high glucose toxicity (Figure
1), suggesting that RhoA-ROCK activation may be a permissive step
in the development of cardiac mechanical defects in response to
high extracellular glucose or diabetic environments.
Our recent study revealed that IGF-1 transgene protected diabetes-induced
mechanical dysfunctions in cardiac myocytes[39] in parallel
to its action on STZ-induced elevation of RhoA mRNA and protein
expression, down-regulation of Kv1.2 channels and activation of
p38 MAP kinase (Ren and colleagues, unpublished data). Our results
did not favor any involvement of another MAP kinase signal molecule
ERK1/2 in diabetes-induced cardiomyocyte dysfunction or the cardiac
protective effect of IGF-1 (Ren and colleagues, unpublished data).
Collectively, these data suggest that up-regulation of the RhoA-ROCK
signal cascade may suppress the expression or function of voltage-dependent
K+ channel and p38 MAP kinase, an route to mechanical
dysfunction in diabetes manifested as prolonged duration of contraction
and relaxation, as well as reduced con-tractility. It is possible
that the beneficial effects of IGF-1 on cardiac mechanical defects
diabetes may be elicited though suppression of activation of the
RhoA-ROCK signal cascade[40,41].
Results from our study suggested likely additional signaling mechanisms
from RhoA and p38 MAP kinase (Ren and colleagues, unpublished data).
Activation of p38 MAP kinase has been speculated to be down-stream
of the ROCK signaling pathway[35]. However, current data
failed to display that an enhanced ROCK I/II mRNA expression in
diabetic groups, indicating that the activity rather than mRNA expression
of ROCK I/II may be involved. Nevertheless, IGF-1 transgene reduced
ROCK I/II mRNA, consistent with the notion that IGF-1 may inactivate
RhoA signal cascade. The lack of effect on ERK1/2 phosphorylation
in response to either diabetes or IGF-1 is somewhat consistent with
our earlier report using the high glucose culture system[42].
RhoA and other cardiovascular complications Ample of evidence
has demonstrated that the RhoA-ROCK mediated signaling pathway plays
an important role in other cardiovascular complications such as
ischemia/reperfusion heart injury and ventricular remodeling following
myocardial infarction. It was reported that fasudil, a potent ROCK
inhibitor, prevented occurrence of myocardial ischemia in patients
with microvascular angina[43]. It was found that ischemia/reperfusion
upregulated RhoA expression in ischemic myocardium and increased
ROCK activity. Inhibition of ROCK with selective ROCK inhibitors
protected the heart against ischemia injury and enhanced post-ischemia
cardiac function. This cardioprotective effect may be attributed
to an anti-apoptotic mechanism of ROCK inhibition since ROCK inhibitors
may significantly attenuate the downregula-tion of Bcl-2 expression
induced by ischemia/reperfusion injury. An alternative explanation
for such cardioprotective property of the ROCK inhibitors may be
associated with their ability to suppress ischemia/reperfusion-induced
elevation in serum levels of proinflammatory cytokines[44].
Further studies have shown that RhoA may be a novel mediator of
adenosine-induced cardiac protection against ischemia. The adenosine
A3 receptor mediated anti-ischemic function in the heart
appeared to signal selectively through RhoA since overexpression
the RhoA-noninteracting mutant caused significant reduction of A3
agonist-induced anti-ischemic effect. It was suggested that RhoA
was an important cardiopro-tective signaling molecule that interacted
directly to phospholipase D (PLD) in cardiac myocytes[45].
Inhibition of ROCK attenuates production of superoxide, reduces
generation of monocyte chemoattractant protein-1 or plasminogen
activator inhibitor-1 (PAI-1), and inhibits activation of macrophages,
neutrophils, and platelets, all of which are considered essential
for inhibition of stress-induced regional inflammatory responses
and diminished myocardial ischemia-reperfusion injury[46].
Furthermore, RhoA was found to mitigate the reperfusion-induced
change in the shape of cardiac capillary endothelial cells in
situ and thereby ameliorate the reperfusion injury[47].
Apart from cardiac ischemia/reperfusion injury, RhoA-ROCK has also
been demonstrated to be involved in the process of myocardial infarction.
It is generally accepted that inhibition of ROCK directly relaxes
vascular smooth muscle and therefore increases regional myocardial
blood flow at sites of major coronary artery stenosis by dilating
abnormally narrowed or occulted artery. However, a recent study
revealed that the infarct-limiting mechanism which involved ROCK
inhibition could be independent of either a change in systemic hemodynamics
or recruitment of collateral blood flow. Transient accumulation
of cAMP was demonstrated in myocardium during ischemic preconditioning
and may play a role to limit the size of infarction[48].
Other mechanisms such as down-regulating inflammatory responses
mediated by cytokines and chemokines may also be involved in limiting
the growth of infarct size[49] although further study
is warranted to elucidate the therapeutic value of ROCK inhibitors
in the management of myocardial infarction.
Summary and conclusion During the past few years, considerable
progress has been made toward understanding the signaling pathways
and the function of RhoA-ROCK in cardiovascular systems. These studies
have convincingly revealed that RhoA-ROCK are versatile signaling
molecules regulating diverse cellular functions including cytoskeletal
rearrangement[50], Ca2+ sensitization[51],
cytokinesis[52] and lineage commitment as well as fate
of stem cells[53]. However, much remains to be learned
about the detailed regulation mechanisms of RhoA-ROCK as well as
its downstream signaling targets. It is imperative that future efforts
be directed toward better defining and characterizing the signal
pathways regulated by RhoA-ROCK in cardiovascular systems. Such
efforts will likely yield new molecular targets for the RhoA-ROCK
signal cascade and ultimately more effective therapies for preventing
or ameliorating cardiovascular diseases such as cardiac hypertrophy,
hypertension, diabetes and atherosclerosis through either pharmacologically
or genetic modulation of RhoA-ROCK regulated signaling.
Acknowledgement
The Ren laboratory has been supported by grants from the American
Diabetes Association, the American Heart Association, the National
Institute of Health, the North Dakota Max Baer Heart Fund, and a
University of Wyoming Research Grant.
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