G ProteinCoupled Receptor Kinases

in Cardiovascular Disease: Why

Where Matters
Fadia A. Kamal, Joshua G. Travers, and Burns C. Blaxall*

Cardiac function is mainly controlled by -adrenergic receptors (ARs), members of the G protein coupled receptor (GPCR) family.
GPCR signaling and expression are tightly controlled by G protein
coupled receptor kinases (GRKs), which induce GPCR internalization
and signal termination through phosphorylation. Reduced -AR density and activity associated with elevated cardiac GRK expression and
activity have been described in various cardiovascular diseases. Moreover, alterations in extracardiac GRKs have been observed in blood
vessels, adrenal glands, kidneys, and fat cells. The broad tissue distribution of GPCRs and GRKs suggests that a keen appreciation of
integrative physiology may drive future therapeutic development. In
this review, we provide a brief summary of GRK isoforms, subcellular
localization, and interacting partners that impinge directly or indirectly
on the cardiovascular system. We also discuss GRK/GPCR interactions
and their implications in cardiovascular pathophysiology. (Trends
Cardiovasc Med 2012;22:213219) 2012 Published by Elsevier Inc.
Introduction
G-protein coupled receptor kinases
(GRKs) are found in nearly all mammalian cells but possess broad and diverse
effects ranging from G protein coupled
receptor (GPCR) signal termination to
transcriptional regulation. Hyper/hypoactivity of GRKs has been correlated
with various human pathophysiologies,
including cardiovascular disease. As their
name implies, GRKs are defined by their
Fadia A. Kamal, Joshua G. Travers, and
Burns C. Blaxall are at The Heart Institute,
Molecular Cardiovascular Biology, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH 45229, USA.
*Address correspondence to: Burns C.
Blaxall, PhD, FAHA, The Heart Institute, Molecular Cardiovascular Biology, Cincinnati
Childrens Hospital Medical Center, Cincinnati, OH 45229, USA. Tel.: (1) 513-8034005; fax: (1) 513-636-5958; e-mail: burns.
blaxall@cchmc.org.
Published online 10 October, 2012.
2012 Published by Elsevier Inc.
1050-1738/$-see front matter

TCM Vol. 22, No. 8, 2012

role in GPCR phosphorylation, receptor

internalization, and signal termination.
Excessive GRK-mediated GPCR phosphorylation leads to receptor desensitization and alternative (GPCR-independent) signaling. As major players in
GPCR-dependent and -independent
signaling pathways, GRKs are becoming attractive therapeutic targets. In
particular, modulating the expression
and/or activity of specific GRKs and
their interacting partners has been
suggested as a novel therapeutic strategy in cardiovascular disease.
GRK Isoforms, Subcellular
Localization, and Interactions
GRKs are classified into three subfamiliesGRK1, GRK2, and GRK4 based
on sequence homology, gene structure,
and tissue expression. The GRK1 subfamily includes GRKs 1 and 7, which are
generally restricted to the retina. The
GRK2 subfamily includes GRKs 2 and 3,
which are ubiquitously expressed, al-

though to varying degrees depending on

the tissue. The GRK4 subfamily includes GRKs 4-6, where GRK4 is found
mainly in the testes and renal tissue
and GRKs 5 and 6 are ubiquitously
expressed. Within the heart, GRKs 2, 3,
and 5 are known to be expressed, with
GRKs 2 and 5 representing the main functional GRKs in the myocardium (Belmonte and Blaxall 2011).
With regard to protein structure, the
GRKs contain three general domains.
An 25amino acid N-terminal tail
unique to the GRK family, a regulator of
G protein signaling (RGS) homology domain, and a catalytic region containing a
Ser/Thr protein kinase domain (Siderovski et al. 1996) are common between
all GRKs. The remaining C-terminal domain is characterized by subtype-specific structural elements that dictate
membrane targeting and subcellular localization of different GRKs. Briefly,
GRKs 1 and 7 have a C-terminus Caax
motif for prenylation and subsequent
membrane recruitment. Membrane localization of GRKs 4 and 6 is a result
of C-terminus palmitoylation, whereas
GRKs 5 and 6 C-terminus lipid-binding
domain facilitates their membrane binding (Pitcher et al. 1996, Stoffel et al.
1994). GRKs 2 and 3 are generally
cytoplasmic and are uniquely targeted
to the membrane from the cytoplasm
in a signaling-dependent manner: Upon agonist stimulation, the activated
G subunits recruit these GRKs to
the agonist-bound GPCR, culminating
in phosphorylation of the receptor
(Pitcher et al. 1992). Finally, sequence
analysis of GRK5 has identified a nuclear localization domain, suggesting
that it may act as an epigenetic regulator; furthermore, accumulation of
GRK5 in cardiac myocyte nuclei promotes cardiac hypertrophy due to its function as a histone deacetylase (HDAC) kinase (Dorn 2009, Huang et al. 2012,
Martini et al. 2008).
Activation of GRKs, initially discovered to function as GPCR kinases, generally requires N-terminusmediated allosteric activation by the agonist-bound
GPCR (Huang and Tesmer 2011), a feature distinguishing them from other serine-threonine protein kinases (Lodowski
et al. 2006). Subsequently, GRK-mediated GPCR phosphorylation, in combination with recruitment of -arrestin to the
receptor, leads to functional repression of
213

Table 1.

Partial list of GRK interacting partners relevant to cardiovascular disease

GRK subtype Interacting partner

GPCR
GRK2

GRK3

-AR

Angiotensin II
receptor
1-AR

GRK4

Dopamine 1 receptor
(D1-R)

GRK5

-AR
Angiotensin II
receptor

Non-GPCR
GRK2

GRK5

PDGFR

Tissue/cells

Reference

Vascular smooth
muscle cells

Phosphorylation induces receptor

desensitization; overexpression in VSMCs
reduces the response to adrenergic
stimulation.
HEK 293 cells
Phosphorylation by GRK2 mediates
receptor internalization.
Isolated cardiomyocytes Cardiac-specific GRK3 inhibition elevates
blood pressure due to increased
sensitivity of the 1-AR to stimulation.
Human renal proximal Phosphorylation induces receptor
tubules CHO cells
desensitization; increased activity of
GRK4 splice variant is associated with
hypertension.
Transgenic mice in vivo GRK5 overexpression reduces cardiac
responsiveness to adrenergic stimulation.
HEK 293 cells
Phosphorylation by GRK5 promotes
activation of ERK.
HEK 293 cells Smooth
muscle cells
Porcine brain extracts

Phosphorylation by GRK2 promotes

receptor desensitization.
Tubulin
GRK2 phoshporylates tubulin in
response to G, linking GPCR activation
to cytoskeletal remodeling.
Glucose transporter 4 3T3-L1 adipocytes
The GRK2 RGS domain sequesters Gq/
11, thus inhibiting this insulin-responsive
transporter.
IRS-1
3T3-L1 adipocytes
Phosphorylation results in receptor
Isolated cardiomyocytes degradation that impairs insulin
signaling.
Class II HDAC
Neonatal rat ventricular GRK5 accumulation in cardiac myocyte
myocytes
nuclei promotes cardiac hypertrophy.
Adult cardiomyocytes

G proteinmediated signaling. GRKmediated phosphorylation of diverse

serine and threonine GPCR residues
creates a specific pattern (or barcode) that controls differential activation of downstream signalinga feature recently termed biased signaling
(Patel et al. 2010). This occurs via
modulating -arrestin scaffolding with
divergent interacting partners (Kim et
al. 2005, Patwardhan and Miller 2007).
For example, phosphorylation of the
angiotensin II receptor by GRK2 and
3 mediated receptor internalization,
whereas phosphorylation by GRK5
promoted activation of the extracellular signal-related kinase (ERK) (Kim et
al. 2005).
Recently, GRKs have been found to
phosphorylate a variety of non-GPCR
proteins, including transcription factors
and tyrosine kinases, further broadening
their functional roles in processes such
214

Effect

as proliferation, development, and immunity. These alternative roles for GRKs

may result from the innate basal activity
of GRKs or perhaps through phosphorylation of proteins located near activated
GPCRs (Usui et al. 2005). So far, the
platelet-derived growth factor receptor
(PDGFR) is the only non-GPCR receptor
whose desensitization is initiated by GRK2dependent phosphorylation, where phosphorylation of the epidermal growth
factor receptor by GRK2 remains with
unknown functional consequences
(Freedman et al. 2002). Targets of GRKs
have also expanded to include cytoskeletal proteins such as tubulin. Phosphorylation of tubulin by GRK2 in response
to G provides evidence that GRK2 is
responsible for transmitting signals
from GPCRs to the cytoskeleton (Haga
et al. 1998, Perrino et al. 2006).
A summary of GRK interacting partners and the resultant downstream ef-

Eckhart et al.
(2002)

Kim et al. (2005)

Vinge et al.
(2008)
Felder et al.
(2002)

Rockman et al.
(1996)
Kim et al. (2005)

Freedman et al.
(2002)
Haga et al.
(1998)
Usui et al. (2004)

Usui et al. (2005)

Ciccarelli et al.
(2011)
Martini et al.
(2008)

fects in cardiovascular signaling pathways is provided in Table 1.

GRKs in Cardiovascular Disease:
Friends or Foes?

Heart
Cardiac contractility is mainly controlled by catecholamines (CAs) that are
locally released into cardiac tissue from
sympathetic neurons or by circulating
CAs that are released from the adrenal
gland. CA levels are increased in response to elevated load or stress on the
heart, where acute physiologic stimulation of cardiac -adrenergic receptors
(-ARs) results in an adaptive increase
in cardiac output, which ultimately activates a negative feedback loop to suppress further catecholamine release. At
the cellular level, agonist-receptor interTCM Vol. 22, No. 8, 2012

actions initiate GRK-mediated -AR desensitization and signal cessation. Clinical and experimental studies suggest
that this GRK-mediated receptor desensitization is initially an adaptive/protective mechanism because chronic -AR
stimulation can be deleterious to the
heart. In the failing heart, diminishing
cardiac output triggers a vicious cycle of
persistent sympathetic activation, resulting in further -AR desensitization
and maladaptive signaling due in large
part to GRK-mediated receptor phosphorylation and loss of responsiveness
to sympathetic stimulation.
Desensitization of the -AR has been
associated with upregulation of GRK2
both at the mRNA level and at the protein level. To explore the role of GRK2 in
the heart, many labs have utilized the technique of genetic manipulation. Interestingly, whereas homozygous knockout of
GRK2 was shown to be embryonic lethal
(Jaber et al. 1996), mice hemizygous for
GRK2 (GRK2/) show increased -AR
mediated cardiac contractility (Rockman et
al. 1998b). Furthermore, overexpression of
GRK2 following ischemia-reperfusion
reduced adrenergic-mediated cardiac
contractility and cardiac function concomitant with increased apoptosis
(Brinks et al. 2010). Conversely, conditional ablation of cardiac GRK2 either
before or 10 days postinfarction reduced
mortality and enhanced cardiac contractility as well as -AR responsiveness
(Raake et al. 2008). Overexpression of
GRK3 had no effect on cardiac sensitivity to -AR stimulation in vivo; however,
cardiac-specific inhibition of GRK3 resulted in elevated systolic blood pressure
due to increased cardiac output, a feature attributed to increased sensitivity of
the 1-AR to stimulation (Vinge et al.
2008). Cardiac overexpression of GRK5
resulted in reduced cardiac responsiveness to adrenergic stimulation (Rockman et al. 1996) along with worsened
cardiac function (Chen et al. 2001), suggesting that GRK5 may impair -adrenergic signaling in heart failure (HF)
(Ping et al. 1997, Takagi et al. 1999).
Although GRK5 upregulation has been
reported in experimental models of HF,
there is currently no evidence of such
upregulation in human HF. In addition,
when GRK5 is excluded from the nucleus, a loss of the myocardial pathological phenotype ensues, suggesting that
TCM Vol. 22, No. 8, 2012

GRK5 subcellular localization plays a

critical role in its function (Martini et al.
2008). A recent study highlighted an additional role for GRK5 in the heart, in
which the L41Q polymorphism, most
abundant in African Americans, was
correlated with reduced mortality from
HF in human patients and was also
shown to be protective against experimental cardiomyopathy in a mouse HF
model (Liggett et al. 2008).
To demonstrate a key role for GRK2 in
the onset and progression of HF, several
strategies have been adopted to suppress
the expression and/or activity of GRK2.
One such strategy employs ARKct, the
C-terminal peptide of GRK2, which competes for binding to G with endogenous
GRK2, thus inhibiting its membrane recruitment and resultant receptor desensitization. ARKct, delivered to the heart
via transgenesis or viral transduction, is
generally effective in preventing cardiomyopathy (Freeman et al. 2001, Harding
et al. 2001, Rengo et al. 2009, Rockman
et al. 1998a, Shah et al. 2001, White et al.
2000) and limiting ischemic injury
(Brinks et al. 2010), as well as normalizing -AR signaling (Eckhart and Koch
2002, Rockman et al. 1998a, Shah et al.
2001, White et al. 2000). For example,
when ARKct is expressed in GRK2/
mice, they demonstrate increased cardiac contractility in response to -AR
stimulation (Rockman et al. 1998b). Recently, a possible alternative mechanism
for the salutary cardiac effects of
ARKct was reported, in which viral
delivery to cultured cardiomyocytes sequestered G and prevented its inhibitory action on the L-type calcium channel (Vlkers et al. 2011). This resulted in
enhanced cardiac contractile responsiveness to -AR agonists with no effect
on -ARmediated cAMP signaling. In a
similar manner, when GRK5 is inhibited
by intracardiac adenoviral expression of
adGRK5-NT, the N-terminal peptide of
GRK5, there is amelioration of HF in the
spontaneously hypertensive rat (SHR)
(Sorriento et al. 2010).
To overcome the various challenges of
large peptide therapeutics, we recently investigated whether small molecules could
be found with efficacy similar to ARKct
and the possible advantage of systemic
delivery. We recently reported the promising effects of small molecule G inhibition in alleviating cardiac dysfunction

in two models of murine HF. These

compounds bind to G and allosterically inhibit its interaction with GRK2
(and a small group of other interacting
partners), thus disrupting downstream
signaling. Improved cardiac function
and reduced hypertrophy were observed, attributed mainly to enhanced
-AR signaling and reduced GRK2 expression and membrane recruitment
(Casey et al. 2010).
Vasculature
Impaired GPCR signaling in the vasculature has a dramatic impact on overall
cardiovascular health. Disruption of 2ARmediated vasodilation, accompanied by vascular GRK2 upregulation,
has been implicated in hypertension in
both human patients and animal models
(Cohn et al. 2008, Cohn et al. 2009,
Eckhart et al. 2002, Feldman 1990, Feldman and Gros 1998, Gros et al. 2000,
Izzo et al. 2008). Interestingly, the properties of -ARs in human lymphocytes
mirror the changes observed in -ARs
from less accessible tissues, allowing clinicians to utilize lymphocytes as valuable tools for the assessment of -AR
function both in hypertension and in HF
(Bonita et al. 2010, Hata et al. 2006,
Oyama et al. 2006). Selective disparity of
GRK2 is observed in hypertensive patients in whom elevated GRK2 activity
and protein expression are not accompanied by variations in GRKs 5 and 6,
protein kinase A, or -arrestins 1 and 2
(Gros et al. 1997).
Targeted overexpression of GRK2 in
vascular smooth muscle cells (VSMCs)
led to a dampened vasodilation, in addition to hypertension, vascular wall thickening, and myocardial hypertrophy
(Eckhart et al. 2002). This overexpression also showed an unexpected attenuation in blood pressure rise in response
to vasoconstricting angiotensin II challenge (Rockman et al. 1996). On the
contrary, the inhibition of GRK2 activity
in the VSM by ARKct or genetic knockdown failed to reduce blood pressure in
a renal stenosis model of hypertension,
despite increased 2-ARmediated vasodilation. This was due to increased 1Dadrenoreceptormediated vasoconstriction that is facilitated by GRK2
inhibition (Cohn et al. 2008). GRK2 has
also been implicated in the disruption of
nonadrenergic endothelial cell nitric ox215

ide synthasemediated vasodilation via

AKT inhibition in portal hypertensive
rats, in which GRK2 knockout restored
nitric oxide production and normalized
portal pressure (Liu et al. 2005). In addition, inhibition of GRK2 (but not
GRKs 3, 5, or 6) resulted in reduced
desensitization of endothelin-induced
Ca2 and IP3 signaling in rat mesenteric
artery smooth muscle cells (resistance
arteries) (Morris et al. 2010).
The second GRK isoform expressed
in VSMCs is GRK5. Vascular-targeted
GRK5 overexpression in mice increased
blood pressure via a Gi-dependent
pathway in a gender-dependent manner
(males more than females). In contrast
to GRK2, overexpression of GRK5 did
not cause vascular or cardiac hypertrophy (Keys et al. 2005). Beyond their
effect on GPCRs, GRK5 has been found
to inhibit vascular endothelial growth
factor receptor signaling, a non-GPCR
interacting partner, in coronary artery
endothelial cells (Zhou et al. 2009). The
role of GRK3, another subtype expressed within the VSM, in hypertension
remains essentially unexplored.

tion of the sympathetic overdrive with

sympatholytic agents such as moxonidine (an imidazole receptor and 2-AR
agonist) increased morbidity and mortality in cardiovascular disease (Clark
and Cleland 2000). This may be partially
due to desensitization of adrenal 2-AR
receptors and the consequent catecholamine hypersecretion.
Aldosterone, a hormone released from
the adrenal cortex and regulated by angiotensin II, is another contributor to HF
pathology. Recently, inhibition of adrenal
GRK2/arr1 biased signaling was shown
to be effective in ameliorating elevated
aldosterone levels and associated cardiac dysfunction in experimental models
of HF (Lymperopoulos et al. 2011).

Kidney
The kidneys play a major role in maintaining normal blood pressure by regulating water and electrolyte transport in

renal proximal tubules via the dopamine

1 receptor (D1-R). Normally, dopamine
stimulation of D1-R invokes a natriuretic response. However, this function
is lost in both animal (Nishi et al. 1993)
and human hypertension (OConnell et
al. 1997) due to D1-R desensitization by
GRK4 in renal proximal tubules (Watanabe et al. 2002); further, GRK4 expression is noted to increase in SHR rats
(Sanada et al. 2006). Single nucleotide
polymorphisms leading to increased kinase activity of the GRK4 splice variant
have been correlated with hypertension
both in human patients and in animal
models (Felder and Jose 2006, Felder et
al. 2002). However, further studies must
be performed to elucidate the structure
and function of GRK4 and its splice
variants to draw a clearer image of its
role in hypertension.
Impaired renal D1-Rs in obesity-induced insulin resistance and the role of
GRKs in that process present another
pathological contributor to HF. Upregu-

Adrenal Gland
An alternative target for HF therapy is the
elevated level of catecholamines within
circulation. Prominent sympathetic nervous system (SNS) hyperactivity stimulates the adrenal glands to secrete excessive amounts of catecholamines from
their medullary chromaffin cells, a process tightly controlled by negative feedback inhibition through adrenal 2-ARs.
Animal models of HF exhibit adrenal
hypertrophy, downregulation of adrenal
2-ARs, and GRK2 upregulation. Adrenal ARKct treatment is able to restore
the inhibitory effect of 2-ARs on adrenal catecholamine release, thus breaking
the pathological cycle of persistent adrenergic stimulation of the heart, resulting in improved cardiac function in
these models (Lymperopoulos et al.
2007). Moreover, recent findings have
correlated the beneficial effects of exercise training in chronic HF to the reduction in adrenal GRK2 expression (Rengo
et al. 2010). Recently, -blocker treatment was found to normalize adrenal
2-AR density and GRK2 expression in a
myocardial infarction rat model (Rengo
et al. 2012). Importantly, central inhibi216

Adrenal

Adrenal

Figure 1. GRKs in cardiovascular disease. (A) Persistent sympathetic stimulation of the cardiomyocyte triggers
GRK2 upregulation that aggravates -AR desensitization and impairs adrenergic signaling. GRK2 upregulation
due to sympathetic nervous system overdrive has also been shown to be involved in the development of insulin
resistance. In the nucleus, GRK5 mediates cardiac hypertrophy by phosphorylating HDAC. (B) The adrenal gland
was recently recognized as an attractive target for HF therapy because adrenal medullary chromaffin cells are the
sites of catecholamine synthesis. GRK2 upregulation has been correlated with elevated catecholamine synthesis
and secretion, primarily due to desensitization of the inhibitory 2-AR receptors. (C) In the adrenal cortex,
angiotensin regulates aldosterone synthesis, where GRK2--arrestin 1mediated signaling interferes with this
regulatory pathway and elevated aldosterone secretion. (D) In the kidneys, dopamine 1-Rmediated natriuresis
is dampened by GRK4; water and sodium retention are key factors of hypertension. (E) In the vasculature,
2-ARmediated vasodilation is impaired by GRK2, leading to hypertension and cardiac and vascular hypertrophy. GRK5 hyperactivity in the vasculature precipitates hypertension.

TCM Vol. 22, No. 8, 2012

lation of GRK4 and, to a lesser extent,

GRK2 is observed in the renal proximal
tubules of obese animals leading to hyperphosphorylation of D1-R and its uncoupling from Gs, provoking impaired
D1-Rmediated natriuresis and hypertension. The pathological processes
were ameliorated by treatment with the
insulin-sensitizing drug rosiglitazone
(Trivedi and Lokhandwala 2005, Umrani
et al. 2002). Although GRK2 may be of
less importance for renal D1-R desensitization, inhibiting GRK2 membrane recruitment or protein expression in insulin-treated kidney cells can normalize
D1-R phosphorylation and function
(Banday et al. 2007).

Insulin Resistance
Diseases such as diabetes, obesity, hypertension, and HF are often associated with
insulin resistance, where reduced tissue
sensitivity to insulin is associated with
metabolic abnormalities. Enhanced SNS
signaling plays a role in the pathogenesis of insulin resistance because -AR
stimulation impairs insulin signaling in
both adipocytes and cardiac myocytes
(Morisco et al. 2006). This occurs
through the sequestering of Gq/11 via
the GRK2 RGS domain, thus inhibiting
the insulin-responsive glucose transporter 4 (Usui et al. 2004). Alternatively,
GRK2 can phosphorylate and desensitize the insulin receptor substrate-1
(IRS-1) in response to chronic stimulation of GPCRs such as the endothelin-A
receptor (Usui et al. 2005). In vitro and
in vivo data have indicated that reduced
GRK2 levels induce enhanced insulin
sensitivity and a lean phenotype and also
protect against tumor necrosis factor-,
a high-fat diet, and aging-induced insulin resistance (Garcia-Guerra et al.
2010), as well as postischemic defects in
myocardial insulin signaling and cardiac
metabolism (Ciccarelli et al. 2011).
These data demonstrate the importance
of GRK2 in the pathology of insulin
resistance.
Conclusions
The vast physiological effects of GRKs
make them an attractive therapeutic target for cardiovascular as well as other
diseases (Figure 1). GRK inhibition has
TCM Vol. 22, No. 8, 2012

been shown to directly ameliorate cardiovascular disease by inhibiting pathological signaling cascades and/or promoting
survival signals. However, detailed information regarding their branching signaling pathways and interacting partners may enable the transition of this
promising therapeutic strategy to the
clinic. Discovery of GRK and/or G
inhibitory agents with a convenient
route of administration and limited side
effects may be a key step in this transition. Considering the pleiotropic and
multiorgan effects of GRK signaling,
systemic GRK inhibition may provide a
superior therapeutic strategy for cardiovascular disease and its comorbidities.
Our data (Casey et al. 2010), as well as
others, suggest that it is possible that
systemic delivery of small molecule inhibitors may ameliorate GRK (or GGRK) mediated pathological signaling
in multiple organs, thus treating cardiovascular disease from several therapeutic angles.

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Challenges in Medical Applications of

Whole Exome/Genome Sequencing
Discoveries
Ali J. Marian*

Despite the well-documented influence of genetics on susceptibility to

cardiovascular diseases, delineation of the full spectrum of the risk alleles
had to await the development of modern next-generation sequencing
technologies. The techniques provide unbiased approaches for identification of the DNA sequence variants (DSVs) in the entire genome (whole
genome sequencing [WGS]) or the protein-coding exons (whole exome
sequencing [WES]). Each genome contains approximately 4 million DSVs
and each exome approximately 13,000 single nucleotide variants. The
challenge facing researchers and clinicians alike is to decipher the biological and clinical significance of these variants and harness the information
for the practice of medicine. The common DSVs typically exert modest
effect sizes, as evidenced by the results of genome-wide association studies,
and hence have modest or negligible clinical implications. The focus is on
the rare variants with large effect sizes, which are expected to have stronger
clinical implications, as in single gene disorders with Mendelian patterns
of inheritance. However, the clinical implications of the rare variants for
common complex cardiovascular diseases remain to be established. The
most important contribution of WES or WGS is in delineation of the novel
molecular pathways involved in the pathogenesis of the phenotype, which
would be expected to provide for preventive and therapeutic opportunities.
(Trends Cardiovasc Med 2012;22:219 223) 2012 Elsevier Inc. All
rights reserved.
Introduction

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Desensitization of human renal D1 dopamine receptors by G protein coupled receptor kinase 4. Kidney Int 62:790 798.

The advent of massively parallel nucleic

acid sequencing or next-generation sequencing (NGS) technologies has had an

White DC, Hata JA, Shah AS, et al: 2000.

Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial
infarction. Proc Natl Acad Sci U S A
97:5428 5433.

Ali J. Marian is at the Center for Cardiovascular Genetics, Brown Foundation Institute
of Molecular Medicine, The University of
Texas Health Science Center and Texas Heart
Institute, Houston, TX 77030, USA.
*Address correspondence to: Ali J. Marian,
MD, Center for Cardiovascular Genetics,
Brown Foundation Institute of Molecular
Medicine, The University of Texas Health
Sciences Center, Texas Heart Institute, 6770
Bertner St, Suite C900A, Houston, TX 77030,
USA. Tel.: (1) 713 500 2350; fax: (1) 713
500 2320; e-mail: Ali.J.Marian@uth.tmc.edu.
Published online 24 August, 2012.
2012 Elsevier Inc. All rights reserved.
1050-1738/$-see front matter

Zhou RH, Pesant S, Cohn HI, et al: 2009.

Negative regulation of VEGF signaling in
human coronary artery endothelial cells by
G protein coupled receptor kinase 5. Clin
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PII S1050-1738(12)00272-1

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TCM

enabling impact in delineating the genetic makeup of each individual. NGS

has raised considerable interest in potential applications of the information
embedded in the DNA sequence of each
genome in the practice of medicine. The
NGS platforms have afforded the opportunity to sequence the entire genome of
an individual (whole genome sequencing [WGS]), which is composed of 3.2
billion nucleotides, within a week. Likewise, it has enabled sequencing of the
entire protein-coding region, referred to
as exome, which is composed of approximately 180,000 exons in approximately
23,500 genes and 30 million nucleotides,
in dozens of individuals within a few
days (whole exome sequencing [WES]).
The enormity of this progress is remark219