(Circulation. 2001;103:1453.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Cardiac Overexpression of a Gq Inhibitor Blocks Induction of Extracellular Signal–Regulated Kinase and c-Jun NH2-Terminal Kinase Activity in In Vivo Pressure Overload
From the Department of Medicine and Cell Biology (G.E., S.V.N.P., A.R., L.M., H.A.R.) and the Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC.
Correspondence to Howard A. Rockman, MD, Department of Medicine and Cell Biology, Duke University Medical Center, DUMC 3104, Durham, NC, 27710. E-mail h.rockman{at}duke.edu
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Abstract |
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Background—Understanding the cellular signals that initiate cardiac hypertrophy is of critical importance in identifying the pathways that mediate heart failure. The family of mitogen-activated protein kinases (MAPKs), including the extracellular signal–regulated kinases (ERKs), c-Jun NH2-terminal kinase (JNK), and p38 MAPKs, may play specific roles in myocardial growth and function.
Methods and Results—To
determine the mechanism of activation of MAPK pathways during the
development of cardiac hypertrophy, we evaluated the induction of MAPK
activity after aortic constriction in wild-type and in 2 types of
cardiac gene-targeted mice: one overexpressing a carboxyl-terminal
peptide of G
q that inhibits
Gq-mediated signaling (TG GqI mouse) and another
overexpressing a carboxyl-terminal peptide of ß-adrenergic receptor
kinase-1 that inhibits Gß
signaling (TG ßARKct mouse). Wild-type
mice with pressure overload showed an acute induction of JNK, followed
by the induction of p38/p38ß at 3 days and ERK at 7 days. Both JNK
and p38 activity remained elevated at 7 days after banding. In TG GqI
mice, hypertrophy was significantly attenuated, and induction of ERK
and JNK activity was abolished, whereas the induction of p38 and p38ß
was robust, but delayed. By contrast, all 3 MAPK pathways were
activated by aortic constriction in the TG ßARKct hearts, suggesting
a role for Gq, but not
Gß.
Conclusions—Taken together, these data show that the induction of ERK and JNK activity in in vivo pressure-overload hypertrophy is mediated through the stimulation of Gq-coupled receptors and that non–Gq-mediated pathways are recruited to activate p38 and p38ß.
Key Words: receptors • kinases • genes • hypertrophy
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although cardiac hypertrophy is thought to be an adaptive response of the heart to a variety of stimuli, it is associated with an increased mortality and increased incidence of heart failure in epidemiological studies.1 2 Understanding the cellular signals that initiate the hypertrophic response is of critical importance in identifying pathways that mediate this maladaptive deterioration. In vitro studies have suggested a pivotal role of Gq-coupled receptor signaling in promoting cardiomyocyte hypertrophy.3 4 Furthermore, cardiac overexpression of Gq-coupled receptors or G
q itself in transgenic mice leads to
myocardial
hypertrophy,5 6
apoptosis,6 7 and
heart
failure.6 7 G protein–coupled receptors (GPCRs) are able to activate mitogen-activated protein kinases (MAPKs) and, under certain conditions, will lead to a mitogenic response.8 9 The MAPK superfamily includes 3 major pathways: the extracellular signal–regulated kinase (ERK)1/2 pathway and 2 stress-activated protein kinase pathways, c-Jun NH2-terminal kinase (JNK) and p38 MAPK.10 Activation of MAPK pathways by growth factors, cytokines, and cell stress selectively mediates a variety of cellular responses ranging from cell growth and differentiation to apoptosis. Studies by Xia et al11 in rat PC-12 pheochromocytoma cells have demonstrated that the dynamic balance between growth factor–activated ERK and stress-activated JNK-p38 pathways may determine whether a cell survives or undergoes apoptosis.
In cell culture studies, it has recently been reported that
although signaling through different G proteins
(Gq, Gi, and
Gs) can selectively activate MAPKs and promote
cell differentiation, stimulation of only
Gq-coupled receptors can equally activate all 3
major MAPK pathways.12
Interestingly, in cultured rat neonatal cardiomyocytes, 2 isoforms of
p38 kinase, p38 and p38ß, appear to have distinct
functions13 : the p38ß
isoform promotes a hypertrophic phenotype, and the p38 isoform tends to
promote an apoptotic
phenotype.13 Furthermore, the
induction of ERK activity in cultured cardiac fibroblasts was found to
be mediated by Gß signals, whereas in cultured cardiac myocytes,
it was
Gq-mediated.14
The important role of GPCRs and MAPK signaling in the
development of cardiac hypertrophy has recently been shown by the
generation of transgenic mice overexpressing
Gq6 15
and the angiotensin type 1
receptor6 15 and by
the adenovirus-mediated transfer of a dominant inhibitory mutant of an
upstream activator of JNK.16
Furthermore, overexpression of a constitutively active mutant of the
transforming growth factor-ß–activated kinase, a member of the MAPK
kinase kinase family, leads to cardiac hypertrophy and dysfunction in
transgenic mice.17 However,
whether Gq-coupled receptor stimulation is
required for the induction of MAPK pathways in in vivo hypertrophy
remains unclear. In this regard, we have recently demonstrated that
inhibition of Gq-coupled receptor signaling in
transgenic mice significantly reduces the hypertrophic response to in
vivo pressure overload.18
Inhibition of Gq signaling was achieved through
overexpression of a carboxyl-terminal peptide of
Gq that inhibits the heterotrimeric
Gq interaction with agonist-occupied receptors.
Although that study showed a critical role for
Gq signals in mediating the hypertrophic
phenotype, it did not identify the downstream cellular pathways
involved.
To determine whether the mechanism for the induction of MAPK
in cardiac hypertrophy is dependent on Gq-
and/or Gß-mediated pathways, we evaluated ERK1/2, p38, p38ß, and
JNK activity during the development of in vivo pressure overload in
wild-type mice, Gq inhibitor transgenic mice (TG
GqI), and transgenic mice overexpressing a peptide inhibitor of Gß
signaling (TG ßARKct, where ßARK indicates ß-adrenergic receptor
kinase).
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Experimental Animals
Adult wild-type and transgenic mice, inbred on a C57/B6 background, were studied at 2 to 3 months of age. The transgenic mice used in the present study were (1) mice with cardiac-specific overexpression of a carboxyl-terminal peptide of G
q that inhibits
Gq-mediated signaling (TG GqI
mice)18 and (2) transgenic
mice with cardiac-targeted overexpression of a peptide inhibitor of
Gß-mediated signaling (TG ßARKct
mice).19 The ßARKct peptide
is composed of the last 194 amino acid residues of ßARK1 and contains
the domain responsible for Gß binding, a process required for
ßARK1 activation.19 The
cardiac phenotypes of the TG GqI and TG ßARKct mice were previously
described for 2 independent
lines,18 19 which
have remained consistent over numerous generations. The animals in the
present study were handled according to approved protocols and animal
welfare regulations by the Institutional Review Board at Duke
University Medical Center.
Transthoracic Echocardiography
Transthoracic 2D guided M-mode echocardiography was
performed in anesthetized mice (2.5% Avertin, 14 µL/g IP)
before and 7 days after the induction of pressure-overload hypertrophy,
with use of an HDI 5000 echocardiograph (Advanced Technology
Laboratories) as previously
described.20 Parameters
measured are shown in the
Table
.
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In Vivo Pressure-Overload Hypertrophy
Mice were anesthetized with a mixture of ketamine
(100 mg/kg) and xylazine (2.5 mg/kg), and transverse aortic
constriction (TAC) was performed as previously
described.21 Sham-operated
mice underwent the same operation except for aortic
constriction.
At 7 hours, 3 days, or 7 days after surgery, sham-operated and banded mice from either the wild-type, TG GqI, or TG ßARKct groups were anesthetized and intubated, and after bilateral vagotomy the trans-stenotic gradient was assessed by recording the simultaneous measurement of right and left carotid artery pressures. Hearts were then excised, and chambers were dissected free, weighed, and then frozen in liquid N2 within 25 seconds from harvesting. Despite identical surgical techniques, a broad range in the ratio of left ventricular (LV) weight to body weight (LVW/BW) is found after TAC, which varies directly with the level of systolic pressure gradient.18 Therefore, to avoid experimental bias, hearts for the MAPK assay from all groups were chosen from animals with a trans-stenotic pressure gradient between 45 and 100 mm Hg, thereby eliminating the high and low extremes.
Immunoblotting
Immunodetection of myocardial levels of MAPKs was
performed on cytosolic extracts from LVs after immunoprecipitation
using polyclonal antibodies to total ERK2-p42/ERK1-p44, p38, p38ß,
and JNK1-p46/JNK3 (Santa Cruz Biotechnology). The kinases were detected
with secondary antibodies conjugated with horseradish peroxidase (ECL,
Amersham Pharmacia Biotech).
MAPK Assays
MAPK assay was performed as previously
described.18 Briefly, 2 mg of
clarified LV extract in 2 mL of RIPA (150 mmol/L NaCl, 50 mmol/L
Tris-Cl [pH 8.0], 5 mmol/L EDTA [pH 8.0], 1% v/v Nonidet P-40,
0.5% w/v deoxycholate, 10 mmol/L NaF, 10 mmol/L sodium pyrophosphate,
100 mmol/L phenylmethylsulfonyl fluoride, 2 µg/mL aprotinin, and 2
µg/mL leopeptin) was immunoprecipitated at 4°C for 2 hours with the
use of antibodies to ERK2-p42/ERK1-p44, p38, p38ß, and JNK1-p46/JNK3
(Santa Cruz Biotechnology) and protein A–agarose or protein G–agarose
(Boehringer-Mannheim). The immunoprecipitates were pelleted and washed
twice with 1 mL of RIPA and twice with 1 mL of kinase assay buffer.
Samples were then resuspended in 40 µL of kinase buffer with 20
µmol/L ATP, [-32P]ATP (20 µCi/mL),
and myelin basic protein (0.25 mg/mL) or glutathione S-transferase
(GST)-c-Jun (10 µg) and incubated at 30°C for 20
minutes.
Reactions were terminated by adding 40 µL of 2x Laemmli loading buffer, and 30 µL of each reaction was electrophoresed through a 15% polyacrylamide/Tris-glycine gel. Phosphorylated myelin basic protein and GST-c-Jun on dried gels were quantified with a PhosphorImager (Molecular Dynamics).
Statistical Analysis
Data are expressed as mean±SEM. One-way ANOVA was
used to evaluate the echocardiographic measurements, heart weight, and
kinase activity data before and after aortic constriction and among
wild-type, TG GqI, and TG ßARKct mice. Post hoc testing was performed
with a Scheffé test. For all analyses, a value of
P<0.05 was considered
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Physiological Response to In Vivo Pressure Overload in Wild-Type and TG GqI Mice
To evaluate the hypertrophic response after TAC, we measured LVW/BW in wild-type and TG GqI mice at 7 hours, 3 days, and 7 days after surgical pressure overload (Figure 1
and
Table
).
Three days after TAC, wild-type mice developed a small but
nonsignificant 16% increase in LVW/BW compared with sham-operated
mice. Seven days after TAC, wild-type mice developed significant LV
hypertrophy with a 54% increase LVW/BW compared with sham-operated
mice. No hypertrophy was detected at 7 hours after TAC.
|
P<0.01 vs 7-day TAC wild type).
In contrast, 3 days after TAC, TG GqI mice developed a
minimal 5% increase in LVW/BW compared with that in sham-operated mice
(Figure 1, P=NS).
Similar to our previous
result,18 the banded TG GqI
mice developed a significantly blunted increase in LVW/BW compared with
that in wild-type mice (22% versus 54%, respectively,
P<0.001;
Table
and
Figure 1) despite a similar trans-stenotic pressure gradient
7 days after TAC (74.4±3.6 mm Hg;
Table
and
Figure 1). No hypertrophy was detected at 7 hours after TAC.
Echocardiography in TG GqI mice showed no change in LV size or percent
fractional shortening after TAC, suggesting the preservation of cardiac
function despite the blunted hypertrophic response
(Table).
Postsurgical mortality in banded TG GqI mice was not different from
that in wild-type mice (19% and 20%,
respectively).
Induction of MAPK Activity With In Vivo
Pressure Overload in Wild-Type and TG GqI Mice
We evaluated JNK, ERK, p38, and p38ß activity 7
hours, 3 days, and 7 days after aortic constriction in wild-type and TG
GqI mice. Data are represented as fold induction in TAC hearts compared
with sham-operated hearts for each of the groups.
JNK Activity
A significant induction of JNK activity, compared with
that after sham surgery, was observed during the initial phase of
pressure overload, as early as 7 hours after TAC, showing the sensitive
nature of JNK activation to acute stress
(Figure 2a and 2b). Interestingly, compared with JNK activity
after the sham operation, JNK activity remained elevated after 3 days
and 7 days of pressure overload during the period of early cardiac
hypertrophy to established cardiac hypertrophy
(Figure 2a and 2b). To determine whether
Gq-mediated pathways are involved in the
induction of MAPK activity, we measured the time course of JNK activity
in TG GqI mice after TAC. As shown in
Figure 2c and 2d, the induction of JNK activity was
completely abolished after acute pressure overload (7 hours) and
remained abolished up to 7 days after pressure overload in the hearts
of TG GqI mice.
|
ERK Activity
The pattern of ERK activity after pressure overload in
wild-type mice differed from the pattern of JNK activity, as shown in
Figure 3a and 3b. Compared with the corresponding
sham-operated hearts, hearts from wild-type mice showed a small
nonsignificant (1.3-fold) increase in ERK activity at 3 days of TAC
that became markedly increased after 7 days of pressure overload.
Similar to the pattern observed for JNK, the banded TG GqI mice showed
that the induction of ERK activity was completely blocked early (3
days) and later (7 days) after TAC
(Figure 3c and 3d).
|
p38 and p38ß Activity
In wild-type mice, a different pattern of activation
for p38 and p38ß by pressure overload was observed compared with that
seen for JNK and ERK. In this case, strong induction of p38 and p38ß
activity was seen as early as 3 days, which remained elevated at 7
days. In contrast, p38 and p38ß were significantly activated in
wild-type hearts compared with sham-operated TG GqI hearts, but only
after 7 days of in vivo pressure overload
(Figure 4b and 4d).
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In all extracts examined, no significant differences were found in total MAPK protein levels between sham operation and TAC for both wild-type and TG GqI mice, as assessed by Western blot, suggesting only a modulation of kinase activities after TAC (data not shown).
MAPK Activation in TG ßARKct Mice
To determine whether a mechanism for the induction of
MAPK activity in cardiac hypertrophy involves Gß subunits released
from either Gq-coupled receptors or from other
GPCRs, experiments were performed in TG ßARKct mice. The ß
subunits of G proteins (Gß) have been shown to activate signaling
pathways in a variety of
cells,22 23
including phosphoinositide 3-kinase (PI3K) in in vivo pressure-overload
hypertrophy.24 Thus, we
tested whether activation of MAPK in hypertrophied hearts involves
Gß. As shown in the
Table,
banded TG ßARKct mice develop cardiac hypertrophy in response to
pressure overload to the same level as found in wild-type
mice.
Heart extracts from sham-operated and 7-day banded TG
ßARKct mice were used to measure MAPK activity. As shown in
Figure 5, a statistically significant increase in activity
for all the MAPKs tested was observed in the banded TG ßARKct hearts
at 7 days after TAC compared with sham-operated TG ßARKct hearts.
Importantly, the level of induction of all 3 MAPK pathways in the TG
ßARKct TAC hearts was similar to that seen in the wild-type TAC
hearts. Taken together, these data suggest a role for
Gq, but not Gß, in the activation of
MAPK pathways with pressure-overload cardiac hypertrophy.
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Basal MAPK activity was evaluated in heart extracts from
sham-operated wild-type, TG GqI, and TG ßARKct mice (n=5 for each
group). No significant difference was found in the basal ERK, JNK, or
p38 ( or ß) activity among the 3
groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we report the time course of induction of all 3 major MAPK pathways (ERK, JNK, and p38) with the development of in vivo cardiac hypertrophy and establish the essential role for Gq signaling in this process. We show that there are 3 phases to the induction of MAPK activity during in vivo hypertrophy. In the first phase (acute pressure overload, 7 hours), only JNK activity is increased. The second phase (early cardiac hypertrophy, 3 days) is associated with robust induction of p38, p38ß, and JNK activity but with a minimal increase in ERK activity. The final phase (established hypertrophy, 7 days) is associated with strong and sustained induction of all the MAPK pathways. This pattern of MAPK activation is markedly altered in the pressure-overloaded TG GqI mice. In this case, JNK and ERK activity are completely abolished, whereas p38 and p38ß activation occurs but is delayed in appearance, suggesting recruitment of other non–Gq-mediated pathways for p38 activation.
In cultured cells, activation of the MAPKs is thought to be
mediated by both and ß subunits of the heterotrimeric G
protein after GPCR
stimulation.25 26 27 28
However, among subunits, only Gq
stimulation has been shown to activate all MAPK
pathways.12 In the rat, Yano
et al29 have recently shown
that angiotensin II–induced cardiac hypertrophy is associated only
with the early and transient activation of JNK. Although the study by
Yano et al suggests that stimulation of the JNK pathway can induce a
hypertrophic response, it did not assess the mechanism for activation
in response to in vivo pressure overload. In the present study, we used
the physiological stimulus of pressure overload and show a specific
pattern of MAPK activation with early and persistent JNK activation,
followed by both p38 and p38ß and then ERK. Furthermore, we show that
all MAPKs are activated by signals originating from
Gq-coupled receptors and that later recruitment
of non–Gq-coupled receptor pathways can
eventually lead to p38 activation once hypertrophy is established.
Finally, it is possible that the strong induction in p38 MAPK activity
in the TG GqI mice, which we show is non–G-protein
(Gq or Gß)–mediated, is responsible for
the mild hypertrophy that develops in these animals with pressure
overload.
A recent study has reported that inhibition of JNK in
the heart by expression of a dominant inhibitory activator mutant can
inhibit the development of cardiac hypertrophy after banding in the
rat.16 The present study adds
to those findings by showing that the development of cardiac
hypertrophy is associated with the induction of all 3 MAPK pathways and
that the increase in activity is mediated through
Gq-coupled receptors. Furthermore, the late
induction of p38 and p38ß MAPK activity in banded TG GqI mice
suggests that non–Gq-mediated pathways or
signaling cascades can be recruited to activate p38 in the
pressure-overloaded heart.30
The non–Gq-mediated induction of p38 is
consistent with a recent study by Zhang et
al17 showing that
overexpression of a constitutively active mutant of transforming growth
factor-ß–activated kinase, a mediator of transforming growth
factor-ß signaling, results in the activation of p38 but not ERK or
JNK MAPK. Also consistent with our findings is the in vitro study by
Sabri et al31 showing that in
mouse cardiomyocytes, p38 MAPK activation was coupled to ß-adrenergic
but not 1-adrenergic receptor
stimulation.
We have previously shown that in TG ßARKct mice, Gß
dimers released from stimulation of Gq-coupled
receptors can activate PI3K24
and that PI3K can activate
MAPK.32 Therefore, we tested
whether released Gß subunits from either Gq
receptors or other GPCRs play a role in the increase in MAPK activity
with hypertrophy. We studied MAPK activity 7 days after TAC in mice
overexpressing the ßARKct, and we have determined that JNK activity
and ERK activity are significantly increased in hearts from TG ßARKct
mice. Although we show that Gq-coupled receptor
stimulation is required for the induction of JNK and ERK activity, by
performing TAC in the TG ßARKct mice, we also demonstrate that
Gß subunits arising from Gq heterotrimers
(or for that matter from any other GPCR) do not significantly
contribute to the induction of the 3 MAPK pathways. Nonetheless,
because the ßARKct transgene is driven by the myosin heavy chain
promoter, we cannot exclude a role for cardiac fibroblasts in the
induction of MAPK activity in cardiac
hypertrophy.14
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Acknowledgments |
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This work was supported in part by National Institutes of Health grants HL-56687 (Dr Rockman) and HL-61690 (Dr Koch). We gratefully acknowledge Debbie Colpitts for her expert secretarial assistance.
Received July 21, 2000; revision received September 14, 2000; accepted September 19, 2000.
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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P. Most, H. Seifert, E. Gao, H. Funakoshi, M. Volkers, J. Heierhorst, A. Remppis, S. T. Pleger, B. R. DeGeorge Jr, A. D. Eckhart, et al. Cardiac S100A1 Protein Levels Determine Contractile Performance and Propensity Toward Heart Failure After Myocardial Infarction Circulation, September 19, 2006; 114(12): 1258 - 1268. [Abstract] [Full Text] [PDF]
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 M. Chiariello and G. Esposito Closing the Cycle: Skp2 Modulates Cyclic Nucleotides Antiproliferative Effects Circ. Res., May 12, 2006; 98(9): 1113 - 1114. [Full Text] [PDF]
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E. Stabile, T. Kinnaird, A. la Sala, S. K. Hanson, C. Watkins, U. Campia, M. Shou, S. Zbinden, S. Fuchs, H. Kornfeld, et al. CD8+ T Lymphocytes Regulate the Arteriogenic Response to Ischemia by Infiltrating the Site of Collateral Vessel Development and Recruiting CD4+ Mononuclear Cells Through the Expression of Interleukin-16 Circulation, January 3, 2006; 113(1): 118 - 124. [Abstract] [Full Text] [PDF]
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 C. Perrino, S. V. Naga Prasad, M. Patel, M. J. Wolf, and H. A. Rockman Targeted Inhibition of {beta}-Adrenergic Receptor Kinase-1-Associated Phosphoinositide-3 Kinase Activity Preserves {beta}-Adrenergic Receptor Signaling and Prolongs Survival in Heart Failure Induced by Calsequestrin Overexpression J. Am. Coll. Cardiol., June 7, 2005; 45(11): 1862 - 1870. [Abstract] [Full Text] [PDF]
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 D. Onan, L. Pipolo, E. Yang, R. D. Hannan, and W. G. Thomas Urotensin II Promotes Hypertrophy of Cardiac Myocytes via Mitogen-Activated Protein Kinases Mol. Endocrinol., September 1, 2004; 18(9): 2344 - 2354. [Abstract] [Full Text] [PDF]
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 L. Barki-Harrington, C. Perrino, and H. A Rockman Network integration of the adrenergic system in cardiac hypertrophy Cardiovasc Res, August 15, 2004; 63(3): 391 - 402. [Abstract] [Full Text] [PDF]
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 G.-X. Zhang, S. Kimura, A. Nishiyama, T. Shokoji, M. Rahman, and Y. Abe ROS During the Acute Phase of Ang II Hypertension Participates in Cardiovascular MAPK Activation But Not Vasoconstriction Hypertension, January 1, 2004; 43(1): 117 - 124. [Abstract] [Full Text] [PDF]
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 J. R. McMullen, T. Shioi, L. Zhang, O. Tarnavski, M. C. Sherwood, P. M. Kang, and S. Izumo Phosphoinositide 3-kinase(p110{alpha}) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy PNAS, October 14, 2003; 100(21): 12355 - 12360. [Abstract] [Full Text] [PDF]
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 E. O. Weinberg, M. Mirotsou, J. Gannon, V. J. Dzau, R. T. Lee, and R. E. Pratt Sex dependence and temporal dependence of the left ventricular genomic response to pressure overload Physiol Genomics, January 15, 2003; 12(2): 113 - 127. [Abstract] [Full Text] [PDF]
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J. R. Keys, E. A. Greene, W. J. Koch, and A. D. Eckhart Gq-Coupled Receptor Agonists Mediate Cardiac Hypertrophy Via the Vasculature Hypertension, November 1, 2002; 40(5): 660 - 666. [Abstract] [Full Text] [PDF]
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J.-M. Li, N. P. Gall, D. J. Grieve, M. Chen, and A. M. Shah Activation of NADPH Oxidase During Progression of Cardiac Hypertrophy to Failure Hypertension, October 1, 2002; 40(4): 477 - 484. [Abstract] [Full Text] [PDF]
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J. Kim, A. D. Eckhart, S. Eguchi, and W. J. Koch beta -Adrenergic Receptor-mediated DNA Synthesis in Cardiac Fibroblasts Is Dependent on Transactivation of the Epidermal Growth Factor Receptor and Subsequent Activation of Extracellular Signal-regulated Kinases J. Biol. Chem., August 23, 2002; 277(35): 32116 - 32123. [Abstract] [Full Text] [PDF]
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D. S. Feldman, A. M. Zamah, K. L. Pierce, W. E. Miller, F. Kelly, A. Rapacciuolo, H. A. Rockman, W. J. Koch, and L. M. Luttrell Selective Inhibition of Heterotrimeric Gs Signaling. TARGETING THE RECEPTOR-G PROTEIN INTERFACE USING A PEPTIDE MINIGENE ENCODING THE Galpha s CARBOXYL TERMINUS J. Biol. Chem., August 2, 2002; 277(32): 28631 - 28640. [Abstract] [Full Text] [PDF]
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J. A. Hill, B. Rothermel, K.-D. Yoo, B. Cabuay, E. Demetroulis, R. M. Weiss, W. Kutschke, R. Bassel-Duby, and R. S. Williams Targeted Inhibition of Calcineurin in Pressure-overload Cardiac Hypertrophy. PRESERVATION OF SYSTOLIC FUNCTION J. Biol. Chem., March 15, 2002; 277(12): 10251 - 10255. [Abstract] [Full Text] [PDF]
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G. Esposito, A. Rapacciuolo, S. V. Naga Prasad, H. Takaoka, S. A. Thomas, W. J. Koch, and H. A. Rockman Genetic Alterations That Inhibit In Vivo Pressure-Overload Hypertrophy Prevent Cardiac Dysfunction Despite Increased Wall Stress Circulation, January 1, 2002; 105(1): 85 - 92. [Abstract] [Full Text] [PDF]
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A. Rapacciuolo, G. Esposito, K. Caron, L. Mao, S. A. Thomas, and H. A. Rockman Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy J. Am. Coll. Cardiol., September 1, 2001; 38(3): 876 - 882. [Abstract] [Full Text] [PDF]
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