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G Protein-Coupled Receptor Regulation in Cardiovascular Disease: Role of G Protein-Coupled…
DOI: http://dx.doi.org/10.5772/.105403
. GRKs in hypertension
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In hypertension, continuous activation of G
AT
mediate vascular smooth muscle contraction and enhance peripheral vascular
1
coupled receptors such as ET
αq
A
and
resistance [46]. Current evidence shows that GRK2 plays an important function in
regulation of prolonged Gαq-related signaling in vascular smooth muscle cells and
consider as the main negative regulator of vasoactive peptide corresponding GPCRs.
Moreover, previously published studies reported that GRK2 negatively regulate ET
and P2Y
receptors in aortic smooth muscle cells [47, 48]. Reported evidence shows
2
A
that inhibition of GRK2 kinase activity diminishes the desensitization process of
AngII/AT
and UTP/P2Y
1
induced arterial smooth muscle contractions [49]. Indeed,
2
published studies show that GRK2 expression is augmented in hypertension, in both
hypertensive animal models and hypertensive patients [50–55]. Therefore, enhanced
GRK2 expression may possibly participate in the pathophysiology of hypertension
development. For instant, GRK2 has been reported to attenuate endothelial NO
production [56]. Furthermore, GRK2 is reported to mediate the desensitization of
β-adrenoceptors, which mediates vasodilation. Thus, enhanced GRK2 expressions
may impair vasodilation in hypertension, which possibly contributes to enhancing
vascular tone and elevation of blood pressure [53]. Additionally, it has been reported
that GRK2 overexpression in vascular smooth muscle cells resulted in a 30% increase
in vascular wall thickness [52], suggesting a possible link between GRK2 overexpression in hypertension and hypertension-induced vascular remodeling [57].
Recently published paper show that elevated GRK2 expression hypertension has a
potential to promote vascular smooth muscle growth and proliferation possibly via
PI3K-Akt signaling, followed by release the GSK3-mediated inhibition of cell cycling
progression, therefore aggravate hypertensive induced pathophysiological vascular
remodeling [58].
Still, it is not clear if the changes in GRK2 expression are a contributing fac
tor for hypertension development or a consequence of hypertension, which needs
further investigation. Moreover, further investigations are required to understand
the molecular mechanisms underlying these changes and how the alterations in GRK
expression implicated in triggering or progression of hypertension might contribute
to the development of novel diagnostic and/or therapeutic strategies to control
hypertension or prevent its complications.
. GRKs in heart failure
Myocardial GRK2 and GRK5 have been shown to be involved in the pathophysiol-
ogy of heart failure [40]. Indeed, several evidences highlight GRK2 as well as GRK5
as the key regulators of β-adrenoceptor [59, 60]. Of importance, recently published
paper describes that GRK2 and GRK5 are new therapeutic targets for pathological cardiac hypertrophy and may attenuate morbidity and mortality rates [61].
Dysregulation of β-adrenoceptor is a pathological characteristic of heart failure; in
particular, the receptors are considerably downregulated and desensitized as a result
of the upregulated levels of GRK2 and GRK5 [16]. Enhanced expression and activity
of GRK2 are associated with the loss of β-adrenoceptor functions that induces deleterious effects in the heart functionality contribute to progression of heart failure [62].
Overstimulation of β-adrenoceptor as a subsequent of continuous sympathetic activation, resulting in GRK and β-arrestins induced desensitization and downregulation of
β-adrenoceptor [63]. Initially, this process is adaptive response to overcome receptor
Novel Pathogenesis and Treatments for Cardiovascular Disease
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overactivation. However, prolonged excessive stimulation mediated receptor downregulation has been reported inducing harmful effect to the heart and consequently
heart failure development [63, 64]. Notably, alterations in GRKs have been observed
in heart failure [39, 65, 66]. Indeed, several evidences highlight GRK2 as well as GRK5
as the key regulators of β-adrenoceptor [59, 60]. Several reported evidence have
shown that GRK2 expression and activity are significantly increased in the failing
heart [39, 67, 68]. Enhanced GRK2 expression and altered functionality have been
found in heart failure status [39, 65, 66, 69]. Moreover, up-regulation of GRK2 level
was detected in end-stage dilated heart failure patient [65]. Even though the mechanism of β-adrenoceptor overstimulation mediated GRK2 upregulation is not clearly
understood, published reports show that GRK2 dysfunction plays an essential function in the pathophysiology of heart failure [70] suggesting that alteration in GRK2
function participates in heart failure pathology. Altered GRK2 expression or activity
appears to contribute to disease progression through various molecular mechanisms.
Therefore, targeting GRK2 expression or inhibition of its activity has been suggested
as a therapeutics strategy for treatment of heart failure patients [71,72].
Reported evidence shows that overexpression of a peptide inhibitor of GRK2;
carboxy terminal domain (βARKct) which lacks to membrane translocation function inhibits GRK2 activity and prevents desensitization of the receptors resulting in
restoring of β-adrenoceptor function and enhanced cardiac contractility in experimental animals of heart failure [73–75]. Moreover, G
-GRK2 inhibition reduces
βγ
pathological effect of myofibroblast activation. Thus, Gβγ-GRK2 inhibition might be
a potential therapeutic strategy to attenuate pathological myofibroblast activation,
interstitial fibrosis, cardiac remodeling, and progression of heart failure [76].
It has been reported that cardiac dysfunction could be attenuated by inhibition
of GRK2 activity [62]. Interestingly, it has been reported that paroxetine, selective
serotonin re-uptake inhibitor (SSRI) approved by FDA for treatment of depression,
significantly inhibited GRK2 kinase activity [49, 77, 78]. Published studies showed
capability paroxetine as GRK2 inhibitor in reversing cardiac remodeling in experimental models of acute myocardial infarction [79, 80]. Therefore, paroxetine may
perhaps be used as a therapeutic approach for targeting GRK2 catalytic activity and
potentially provide a protective role against cardiac hypertrophy development via its
function as GRK2 inhibitor.
GRK5 another GRK member that mediates phosphorylation and desensitization
of β-adrenoceptor is well known to regulate heart functions [72]. Several studies
suggest that GRK5 plays a crucial role in various cardiovascular diseases. For instance,
previous studies show that GRK5 overexpressing mice developed cardiac hypertrophy, which rapidly progressed to heart failure [81]. Moreover, GRK5 knockout mice
showed attenuated hypertrophic responses [82]. Furthermore, GRK5 overexpressing
mice showed an alteration in myocardial performance including attenuation of contractility, cardiac output, stroke work, and stroke volume [83]. Of note, GRK5 levels
were shown to be markedly elevated in heart failure patients and patients with left
ventricular volume overload disorders and dilated cardiomyopathic hearts [84–86].
GRK5 overexpressed transgenic mice exhibited enhanced susceptibility to
pressure overload-induced cardiac hypertrophy and cardiac dysfunction [87].
Furthermore, cardiac-specific GRK5 transgenic mice demonstrated reduced cardiac
function and increased adverse cardiac remodeling in a myocardial infarctioninduced heart failure mice model [64]. On other hand, heart hypertrophic responses
were attenuated in GRK5 knockout mice [88], these studies demonstrated the possible
functions of GRK5 in pathological cardiac remodeling development. Interestingly,
G Protein-Coupled Receptor Regulation in Cardiovascular Disease: Role of G Protein-Coupled…
DOI: http://dx.doi.org/10.5772/.105403
several lines of evidence show that GRK5 can translocate to the nucleus, exerting its
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non-canonical functions. For instance, it was shown that GRK5 in the cardiomyocyte nuclei acts as a class II histone deacetylase (HDAC) kinase, phosphorylating
HDAC5 and leading to de-repression of myocyte enhancer factor 2 (MEF2)-mediated
hypertrophic gene transcription [81, 89]. In addition, it was demonstrated that GRK5
interacts with hypertrophic transcription factors like nuclear factor of activated T cell
(NFAT) and nuclear factor κ-B (NF-κB) [81, 87, 90, 91]. These studies indicate that
GRK5 has a major role in the pathogenesis of the cardiovascular disorders and GRK5
might be a therapeutic target for heart failure. Recently, it has been demonstrated that
KR-39038, a novel small molecule inhibitor of GRK5, significantly inhibited cellular
hypertrophy and HDAC5 phosphorylation in neonatal rat ventricular myocytes. This
inhibitor was able to minimize the left ventricular weight, improve cardiac function
and ameliorate myocardial remodeling in animal model of heart failure [92]. Another
important agent proposed as a GRK5 inhibitor is an anti-inflammatory and anti-allergic immunomodulator, named amlexanox [93]. This agent was able to inhibit GRK5
induced MEF2 activation in neonatal rat ventricular myocytes and inhibit GRK5
mediated HDAC5 phosphorylation in cellular model of cardiac hypertrophy [93, 94].
. GRKs in myocardial infarction
It has been reported that GRK2 expressions upregulated in peripheral blood
lymphocytes in patients with acute ST-segment elevation myocardial infarction.
Enhanced lymphocyte GRK2 expressions are associated with worse cardiac functionality. These studies indicate that GRK2 could be predictive of myocardial remodeling
after myocardial infarction [95, 96]. Enhanced GRK2 levels and activity are deleterious to post-ischemic myocardium in acute ischemia/reperfusion (I/R) injury animal
model [97]. It has been reported that GRK2 peptide inhibitor; βARKct provides
cardioprotective effect, which modulate GRK2-mediated PI3K-Akt-NOS signaling pathway in the ischemic heart which validates GRK2-related effect on survival
and apoptotic signaling in the ischemic heart [97]. βARKct expression mediated
GRK2 inhibition modulate Akt downstream pro-survival signaling such as reduced
Caspase-3 activity, increased eNOS activation and NO production and then reduced
apoptosis and cell death [97]. Furthermore, decreasing GRK2 expression in cardiomyocytes attenuate myocyte apoptosis possibly via Akt/Bcl-2 mediated mitochondrial protection and limits I/R- provoked injury and improves post-ischemia recovery
in the heart [98]. Additionally, it has been reported that fibroblast specific GRK2
knockout has a protective effect after myocardial I/R injury in mice. GRK2 fibroblast
knockout mice decreased the infarct size, increased ejection fraction, preserved
cardiac function, and also reduced tumor necrosis factor-α expression, fibrotic gene
expression, and fibrosis development [99].
. Conclusions
Cardiovascular diseases are a leading cause of death worldwide. The patho-
physiological mechanisms are regulated by a GPCR mediated complex network of
transduction pathways. The functions of GRKs, negative regulators of GPCR, are
not limited to receptors desensitization. It is expanded further to activations of many
transductions in non-classical manner. As the expression and kinase activity of GRK2
and GRK5 are altered in cardiovascular diseases, Therefore, better knowledge of the
Novel Pathogenesis and Treatments for Cardiovascular Disease
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sduction events which mediated by up-regulated GRK2 and/or GRK5 in terms
tran
of the expression, activity, and localization would help to develop a novel strategy
for targeting their expressions or inhibiting activity. This will participate in building a knowledge-based platform identifying a new therapeutic target to prevent
the progression of cardiovascular diseases. Many different approaches could be
applied, including small molecule inhibitors, gene therapy, and the use of advanced
drug delivery systems to potentially prevent the progression of cardiovascular
disease. Overall, GRKs play an important role in cardiovascular diseases progression.
Pharmacological intervention of GRK5 as well as GRK2 would provide a novel possible future target for cardiovascular disease progression prevention.
Acknowledgements
The authors extend their appreciation to the Deputyship for Research &
Innovation, Ministry of Education in Saudi Arabia for funding this research work
through project no. (IFKSUDR_H150).
G Protein-Coupled Receptor Regulation in Cardiovascular Disease: Role of G Protein-Coupled…
DOI: http://dx.doi.org/10.5772/.105403
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