(Circulation. 2001;103:2973.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Ablation of Serotonin 5-HT2B Receptors in Mice Leads to Abnormal Cardiac Structure and Function
From the Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch (C.G.N., P.H., N.M., J.L.V., L. Maroteaux); the Faculté de Médecine, Strasbourg (M.P.D., L. Monassier); CNRS, Faculté de Pharmacie, Illkirch (K.G., R.M., R.A.); and Centre de Recherches Claude Bernard, Service de Biochimie, Hôpital Lariboisière, Paris (P.M., J.-M.L.), France.
Correspondence to Luc Maroteaux, IGBMC, BP 163, 67404 Illkirch Cedex, France. E-mail lucm{at}igbmc.u-strasbg.fr
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Abstract |
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Background—Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. Because little is known about the molecular mechanism of cardiac functions triggered by serotonin, the link between downstream signaling circuitry of its receptors and the heart physiology is of widespread interest. None of the serotonin receptor (5-HT1A, 5-HT1B, or 5-HT2C) disruptions in mice have resulted in cardiovascular defects. In this study, we examined 5-HT2B receptor–mutant mice to assess the putative role of serotonin in heart structure and function.
Methods and Results—We have generated Gq-coupled 5-HT2B receptor–null mice by homologous recombination. Surviving 5-HT2B receptor–mutant mice exhibit cardiomyopathy with a loss of ventricular mass due to a reduction in number and size of cardiomyocytes. This phenotype is intrinsic to cardiac myocytes. 5-HT2B receptor–mutant ventricles exhibit dilation and abnormal organization of contractile elements, including Z-stripe enlargement and N-cadherin downregulation. Echocardiography and ECG both confirm the presence of left ventricular dilatation and decreased systolic function in the adult 5-HT2B receptor–mutant mice.
Conclusions—Mutation of 5-HT2B receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT2B receptor is required for cytoskeleton assembly to membrane structures by its regulation of N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via the 5-HT2B receptor, regulates cardiac structure and function.
Key Words: cardiomyopathy • cell adhesion molecules • genetics • serotonin
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Introduction |
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Cardiomyopathy is an important risk factor for subsequent cardiac morbidity and mortality. Relatively little is known about the molecular mechanism underlying cardiomyopathy and heart failure. The neurohormone serotonin (5-hydroxytryptamine, 5-HT) is involved in blood pressure regulation and cardiac function in adults. 5-HT plays an important role in hemodynamic stability. 5-HT–specific reuptake inhibitors (by increasing the availability of 5-HT) produce arrhythmia, including atrial fibrillation, bradycardia, and heart block.1 The mitogenic action of 5-HT2 triggers the valvular fibroplasia observed in carcinoid patients3 and in obese people taking the 5-HT uptake inhibitor/5-HT2B receptor ligand fenfluramine as an appetite suppressant.4 5
The various biological actions of 5-HT are mediated by numerous cognate receptors. There are at least 15 receptor subtypes that belong to 4 classes: 5-HT1/5, 5-HT2, 5-HT3, and 5-HT4/6/7.6 5-HT binding to 5-HT2A, 5-HT2B, or 5-HT2C receptors activates phospholipase C, releases inositol trisphosphate, and increases intracellular calcium levels. 5-HT2B receptor is involved in 5-HT–induced mitogenesis in which c-Src is required for cell cycle progression via the mitogen-activated protein kinase pathway.7 Stimulation of the 5-HT2B receptor results in cross talk with the 5-HT1B/1D receptor subtype via activation of phospholipase A2.8 The 5-HT2B receptor also activates nitric oxide synthesis through a PDZ domain.9
To understand the specificity of each receptor subtype, the genetic inactivation approach in mice was used. Mutation of 5-HT receptors 5-HT1A, 5-HT1B, or 5-HT2C in mice leads to behavioral abnormalities.10 We have recently shown that 5-HT2B receptor inactivation in mice leads to trabeculation defects in embryonic heart, causing a 30% lethality at midgestation.11 Now, we investigated cardiopathy in surviving 5-HT2B receptor–mutant mice. This study reveals that 5-HT via the 5-HT2B receptor is involved in the regulation of cardiomyocyte cytoarchitecture and function. 5-HT2B receptor ablation in mice leads to cardiomyopathy, including left ventricular (LV) dysfunction without hypertrophy.
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Methods |
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Generation of 5-HT2B Receptor–Knockout Mice
Targeted mutagenesis by homologous recombination was described previously.11 All animal experimentation was performed in accordance with institutional guidelines, and protocols were approved by the French Animal Care Committee in accordance with European regulations.
Morphological Analysis of Mouse
Embryos
Transmission electron microscopy and
histological techniques were performed as previously
described.12
Immunohistochemistry was performed on heart cryosections with the
anti–sarcomeric myosin heavy chain (MHC) antibody (MF-20).
Anti-tropomyosin and N-cadherin antibody reactions were performed on
paraffin sections as
described.11 Signal
intensity was quantified with a fluoroimager (Typhoon, Molecular
Dynamics) and calculated as the product of averaged pixel intensity
per area.
Cardiomyocyte Density Determination and
Confocal Microscopic Analysis
Confocal microscope images of the sections were taken
on a Leica TCS4D. Total numbers of nuclei per field were calculated by
counting propidium iodide–stained nuclei. Nonmyocytes were
tabulated by counting the number of nuclei not surrounded by
cytoplasmic myosin, and this number was used to calculate total
myocytes as
described.13
Analysis of Hypertrophic Cardiac
Genes by RT-PCR
Semiquantitative reverse transcription–polymerase
chain reaction (RT-PCR) was performed on 1 µg of total RNA extracted
from age-matched control and knockout mice with the ribosomal
elongation factor 1A used as an internal control as previously
described.11 The following
primers were used: atrial natriuretic factor (ANF),
5'-CCAGGCCATATTGGAGCAAA-3' and
5'-GAAGCTGTTGCAGC-CTAGTC-3';
GATA4, 5'-CACTATGGGCACAGCAGCTCC-3' and 5'-TTGGAGCTGGCCTGCGATGTC-3';
-MHC,
5'-CTGCTGGAGAGG-TTATTCCTCG-3'
and 5'-GGAAGAGTGAGCGGCGCATCAAGG-3'; and ß-MHC
5'-TGCAAAGGCTCCAGGTCTGAGGGC-3' and
5'-GCCAACACCACCCTGTCCAAGTTC-3'. The PCR products were
quantified with an image analyzer
(Bio-Rad, GS-700) and calculated as arbitrary
units.
Cardiomyocyte Isolation and Video
Imaging
Ventricular cardiomyocytes
from newborn mice were isolated as previously
described.14 Beating rate in
response to dobutamine was determined by video
recording of isolated cardiomyocytes. The
analysis was performed on the stage of an inverted microscope
(Leica DMRiB) with software developed by J.-L.V.
Echocardiographic Methods
Animals (19-week-old mice) anesthetized with
sodium pentobarbital (30 mg/kg IP) were observed with 2D-guided M-mode
echocardiograms with a short-focal-length, 12-MHz
(Hewlett-Packard Medical Systems) transducer. LV
end-systolic and end-diastolic diameters (LVESD and
LVEDD, respectively) were measured. The percentage of LV fractional
shortening was then calculated.
Blood Pressure Measurements
Systolic arterial pressure and
heart rate were recorded by the tail-cuff technique with the LE5002
Storage Pressure Meter (Letica) in awake 19-week-old mutant and control
mice.
Electrocardiogram
Nineteen-week-old mice anesthetized with
tribromoethanol (2.5% solution, 13 µL/g body wt SC) were
recorded with the 4 arms of the ECG leads attached at the origin of
each paw by unipolar and bipolar lead derivations. The signal was
recorded by an ECG (EKG-Burdick, Siemens) connected to a data
acquisition system (MP100 and Acknowledge Software, Biopac Systems
Inc).
Isolated Perfused Heart Preparation
Hearts from mice (12 to 19 weeks old, 23 to 25
g) anesthetized with sodium pentobarbital (60 mg/kg IP) and
heparinized (500 U/kg IP) were cannulated and perfused according to
Langendorff at 37°C and pH 7.4 with modified Krebs-Henseleit solution
containing (mmol/L) NaCl 118, NaHCO3 24, KCl
4.7, KH2PO4 1.2,
MgSO4 1.2, CaCl2 2.5,
disodium EDTA 0.5, and glucose 10, gassed with 95%
O2/5% CO2. Perfusion
pressure was constant and equivalent to 100
cm H2O. The diastolic tension of
the suture was adjusted to 1 g during the stabilization period of
the heart.
Measurement of Markers for Cardiac Failure and
Myocardial Damage
Enzyme immunoassay for creatine kinase-MB isoenzyme
and for cardiac troponin I was determined from samples of serum from
adult
mice.15
Data Analysis and Statistics
All values represent the average of
independent experiments±SEM (n=number of experiments as indicated in
the text). Comparisons between groups were performed with Student’s
unpaired t test or ANOVA and a
Fischer test. Significance was set at
P<0.05.
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Results |
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Heart Morphology
5-HT2B receptor inactivation leads to partial embryonic death due to trabecular defects in the heart leading to midgestation lethality (30%, n=120).11 The 5-HT2B receptor–mutant mice that reached birth displayed no obvious defects, although 30% (n=120)11 of newborn mice developed signs of fatigue and dyspnea between postnatal days 2 and 5 and died within 24 hours from the onset of these symptoms. A likely cause of neonatal death is inadequate cardiac output due to hypoplasia of the LV, despite the lack of evidence for pulmonary edema. All 5-HT2B receptor–mutant mice that survived the first postnatal week developed to adulthood with cardiac problems. This variation in severity of the phenotype could not be attributed to variability in the genetic background of the mice (all the findings were obtained from 129/PAS pure background mice, and similar mortality was also observed on a C57/Black6J-129/PAS mixed background).
Newborn 5-HT2B receptor–mutant
hearts display a striking decrease in the ratio of heart to body weight
(28%). This difference was 24% in 6-week-old mutants
(Table 1
). Histological
analysis demonstrated that the decrease in heart mass was
restricted to the ventricles (as shown in
Figure 1A).
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Cardiomyocyte Number and Size
The ratio of cardiomyocytes to total cells
(stained with MF-20 antibody, myocyte-specific MHC, and propidium
iodide, respectively) revealed 15% fewer
cardiomyocytes in the newborn mutants, as shown in
Figure 1B
.
Isolated mutant cardiomyocytes are 12% shorter than
wild-type (n>15)
(Figure 1C). The decrease in ventricular mass
observed in 5-HT2B receptor–mutant mice
results, therefore, from decreases in both cell density and size of
cardiomyocytes.
Hypertrophic Gene Expression in Heart
To determine whether the loss of
ventricular mass creates compensatory hypertrophic growth
associated with altered expression of hypertrophic
markers,16 ANF, -MHC,
ß-MHC, and GATA4 expression was evaluated in 12-week-old mutant
hearts. Semiquantitative RT-PCR analysis of mutant heart mRNA
demonstrated that none of these mRNAs showed significant variation in
expression level (<5% variation compared with control, n=5 different
individuals). Similar results were obtained in newborn mutants (data
not shown).
Cardiomyocyte Function
To determine whether the cardiac phenotype of
5-HT2B receptor–mutant mice was cell-intrinsic,
the function of spontaneously beating isolated
cardiomyocytes from newborns was investigated. The
ß-adrenergic receptor agonist dobutamine increased the
beating rate of wild-type cardiomyocytes in a
dose-dependent manner. Mutant cardiomyocytes, however,
exhibited an impaired response to dobutamine in the absence
of sympathetic innervation
(Figure 2), indicating cell autonomous
defects.
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Ultrastructural Analysis
A loss of myocardial organization, a scattered area of
degenerated cardiomyocytes, and myofibrillar disarray were
apparent in newborn mutant hearts. Wavy myofibrils were identified by
anti-tropomyosin staining
(Figure 3A). In this area, myofilaments appeared misaligned,
I bands were not detectable, abnormally wide Z bands were seen, and
mitochondria were rounded and irregular
(Figure 3B). The sarcomere length in mutants is 33% smaller
than that in control mice (n=25). Notably, no evidence for myocardial
apoptosis, fibrosis, or significant inflammatory cell
infiltrates was found. Nearly identical histopathological findings were
observed in all adult mutant hearts.
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Furthermore, 5-HT2B receptor–mutant
cardiomyocytes had reduced numbers of adherens junctions
(Table 1), and the intercalated disks were
consistently disorganized
(Figure 4A). Z line–associated protein expression was
investigated. Vinculin staining in mutant newborn ventricles was
unaltered (not shown). N-cadherin expression, however, was reduced by
38.8% in mutant myocardium
(Figure 4B, Table 1).
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Hemodynamic
Measurements
Transthoracic echocardiograms
(Figure 5A, Table 2) show LV dilation and reduced systolic
performance of the adult mutant mice. In male mutants, the
LVEDD was 25% higher than wild-type. Extreme LV dilation (increased
LVEDD) was observed, and the LVESD was increased by 50% in male
5-HT2B receptor mutants (n>4). The percent of
LV fractional shortening, as an indicator of systolic cardiac
function, was significantly decreased in male (20%)
(Figure 5A, Table 2) but not in female mutants (not shown). When
myocardial function was measured by Langendorff’s heart preparation in
vitro, however, the developed force in response to adrenergic stimuli
(isoproterenol) was also significantly reduced in female mutants
(Table 2,
Figure 5B). A slight decrease in mutant female
coronary flow was also observed, whereas no apparent change in
basal blood pressure or heart rate was detected
(Table 2).
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ECG Analysis
ECG analysis in mutants revealed neither
atrioventricular nor
intraventricular conduction defects (similar PR
intervals, QRS duration, and amplitude). The resting heart rate was
significantly decreased in the anesthetized female mutants. The
P duration, but not P amplitude, was significantly increased in female
(47%) and to a lesser extent in male (17%) mutants. The most striking
difference between wild-type and 5-HT2B receptor
mutants (both female and male) was dramatically elevated T-wave
amplitude, which is an indicator of abnormalities in repolarization of
ventricles
(Figure 5C, Table 2). Serum potassium levels, however, were not altered
(not shown).
Biochemical Markers of Heart Failure
Clinical indications of human acute myocardial
infarction and injury are revealed by serum levels of the
cardiac-specific biochemical markers troponin I and creatine
kinase-MB.15 Strikingly
elevated markers were observed in the serum of
5-HT2B receptor mutants (6 weeks old)
(Figure 5D). Interestingly, male
5-HT2B receptor mutants exhibited more
pronounced biological changes than
females.
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Discussion |
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In this study, we provide the first evidence that Gq-coupled 5-HT2B receptor ablation in mice leads to cardiomyopathy with LV dysfunction, dilation, and an abnormal structure within the Z band correlated with a deficiency in N-cadherin expression.
5-HT2B receptor–mutant mice exhibit
thinning of the ventricular wall and a reduction in
ventricular mass that appears to be due to 2 complementary
mechanisms: loss of myocardial cells and decrease in cell size. The
primary loss of myocardial cells could be due to apoptosis
and/or impaired proliferation of cardiomyocytes. No
apoptotic bodies were observed by transmission electron
microscopy, yet mitogen-activated protein kinase (MAPK/ERK)
activation in response to 5-HT was strongly reduced in newborn mutant
hearts (unpublished observations). Together, these data suggest that
ventricular hypoplasia is mainly due to impaired
proliferation, not to apoptosis. Mutation of the thin-filament
protein troponin T in mice also results in
cardiomyopathy due to a primary loss of
cardiomyocytes and decrease in cell
size.13 Myofibril loss is
the most obvious structural change in human
cardiomyopathy,17
and sarcomeric disarray is characteristic of failing
hearts.18 Actually, the
decrease in cardiomyocyte size could be due to impaired
growth during postnatal development. The loss of
ventricular mass creates biomechanical stress on the
remaining viable heart muscle, which typically triggers a hypertrophic
response by inducing embryonic gene reexpression. In the
5-HT2B receptor–mutant heart, however, despite
increased preload conditions (increased LVEDD), the expression of
hypertrophic markers was not elevated, and there were no morphological
signs of hypertrophy. Unlike the
5-HT2B receptor–mutant mice, -MHC– and
myf5-mutant mice develop hypertrophy, and
interstitial fibrosis accompanied
cardiomyopathy.19
Why 5-HT2B receptor mutants fail to have a
hypertrophic response remains to be investigated. Combined myofibrillar
breakdown and inhibited myofibrillogenesis may account for loss of
ventricular mass without substantial
hypertrophy. Mice overexpressing
tropomodulin20 or mutated
troponin T are models of dilated cardiomyopathy
with inhibited myofibrillogenesis without a hypertrophic
response.13
Other neurotransmitters and hormones that use
Gq protein signaling are also involved in
cardiomyopathies. In vitro and in vivo studies have
indicated a role for hormones such as angiotensin II,
bradykinin
B2,21
endothelin 1, norepinephrine, and prostaglandin
F2, not only in stimulation of cardiac
hypertrophy but also in decompensation of the hypertrophied
heart through induction of cardiomyocyte
apoptosis.22
Targeted expression of the carboxy-terminus of the -subunit of
Gq or overexpression of the
Gq protein in the heart causes
cardiomyopathy. The regulation of
cardiomyocyte cytoarchitecture through the
Gq-coupled pathway, however, is poorly
understood.
Our data suggest that alteration in
cardiomyocyte cytoarchitecture results from
5-HT2B receptor mutation. How does the
5-HT2B receptor affect the organization of
myofibrils and related cardiomyocyte cytoarchitecture?
5-HT2B receptor–mutant
cardiomyocytes exhibit abnormal organization of contractile
elements, including Z-stripe enlargement
(Figure 5). Interestingly, most of the mutations leading to
dilated cardiomyopathy in humans affect structural
proteins involved in cytoskeleton–extracellular matrix interaction at
the Z stripe.23 The altered
intercalated disk structures observed in the hearts of
5-HT2B receptor–mutant mice could be a
molecular mechanism leading to impaired contractility
and myofibrillar degeneration. Z line–associated structures are
responsible for the lateral alignment of myofibrils, and their
anchorage is at N-cadherin– and vinculin-containing costameres along
the cell membrane. The 5-HT2B receptor–mutant
mice exhibit decreased N-cadherin levels. N-Cadherin plays an important
role in maintaining myofibril
integrity,24 in
cardiomyocyte interaction, and in
myofibrillogenesis.25
Downregulation of N-cadherin and disruption of intercellular adhesion
have also been reported in failing guinea pig
hearts.26 Addition of
antibodies against N-cadherin to cardiomyocyte cultures
also induces myofibrillar and cytosolic
disorganization.27
Furthermore, mutation of the
Drosophila 5-HT2Dro receptor (a
pharmacological orthologue to 5-HT2B receptor)
results in embryos that do not gastrulate properly because of changes
in E-cadherin–dependent cell
adhesiveness.28 Our data
suggest that the 5-HT2B receptor in mammals is
required for proper myofibril integrity and myofibrillogenesis by
regulating N-cadherin expression.
The 5-HT2B receptor–mutant mouse
phenotype has similarity to the natural history of patients
with dilated cardiopathy. LV dilatation and depressed LV
systolic performance in the mutant mice are typical
features used to diagnose dilated cardiomyopathy in
humans. Moreover, serum biochemical indicators of myocardial infarction
are increased in the 5-HT2B receptor–mutant
mice. No apparent changes in basal blood pressure and heart rate are
detected
(Table 2), suggesting that either the
5-HT2B receptor is not involved in basal blood
pressure control or systemic vascular flow redistribution compensates
at least partially for this impaired
contractility.
5-HT2B receptor–mutant mice exhibit sex differences: Consistent with the idea that the morphological lesions detected in male mutant mice underlie abnormal functions, female mutant mice with less severe histopathological findings did not reveal significant functional changes under steady-state conditions. Similar sex differences occur in other cardiomyopathy models, such as in the ß-MHC–mutant mouse.29 In X-linked cardiomyopathy in humans, heart failure occurs rapidly after onset of symptoms in males but is delayed in its onset and progression in females.30 Cardioprotective effects in females have been attributed to estrogen action.
The 5-HT2B receptor–specific agonist norfenfluramine, ergot drugs, and 5-HT released from carcinoid tumors contribute to valvular fibroplasia in humans.4 5 The lack of detectable valvular defects in mutant mice, however, indicates that the 5-HT2B receptor is not required for heart valve development.
Mutation of a noncytoskeletal molecule, the 5-HT2B receptor, provides the first genetic evidence that 5-HT, via this receptor, regulates cardiomyocyte function and structure. These findings should facilitate a genetic approach and new avenues of drug design in fighting cardiovascular disease.
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Acknowledgments |
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This work was supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Hôpital Universitaire de Strasbourg, the Université Louis Pasteur, and by grants from the Fondation de France, the Fondation pour la Recherche Médicale, the Association pour la Recherche contre le Cancer (9503, 7389), the Ligue Nationale contre le Cancer, and a Lilly–Université L. Pasteur Fellowship (Dr Nebigil). We wish to acknowledge Dr K. Niederreither for stimulating discussions and a critical reading of the manuscript.
Received December 1, 2000; revision received February 7, 2001; accepted February 16, 2001.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Sheline YI, Freedland KE, Carney RM. How safe are serotonin reuptake inhibitors for depression in patients with coronary heart disease? Am J Med. 1997;102:54–59.[Medline] [Order article via Infotrieve]
2. Yavarone MS, Shuey DL, Tamir H, et al. Serotonin and cardiac morphogenesis in the mouse embryo. Teratology. 1993;47:573–584.[Medline] [Order article via Infotrieve]
3.
Robiolio PA,
Rigolin VH, Wilson JS, et al. Carcinoid heart disease: correlation of
high serotonin levels with valvular abnormalities
detected by cardiac catheterization and
echocardiography.
Circulation. 1995;92:790–795.
4.
Fitzgerald LW, Burn
TC, Brown BS, et al. Possible role of valvular
serotonin 5-HT2B receptors in the cardiopathy associated
with fenfluramine. Mol
Pharmacol. 2000;57:75–81.
5.
Rothman RB, Ayestas
MA, Dersch CM, et al. Aminorex, fenfluramine, and chlorphentermine are
serotonin transporter substrates: implications for primary
pulmonary hypertension.
Circulation. 1999;100:869–875.
6. Hoyer D, Fozard JR, Saxena PR, et al. IUPHAR classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev. 1994;46:157–203.[Abstract]
7.
Nebigil CG, Launay
J-M, Hickel P, et al. 5-Hydroxytryptamine 2B receptor
regulates cell-cycle progression: cross talk with tyrosine kinase
pathways. Proc Natl Acad Sci
U S A. 2000;97:2591–2596.
8.
Tournois C, Mutel
V, Manivet P, et al. Cross-talk between
5-hydroxytryptamine receptors in a serotonergic cell
line: involvement of arachidonic acid
metabolism. J Biol
Chem. 1998;273:17498–17503.
9.
Manivet P,
Mouillet-Richard S, Callebert J, et al. PDZ-dependent activation of
nitric-oxide synthases by the serotonin 2B receptor.
J Biol Chem. 2000;275:9324–9331.
10. Murphy DL, Wichems C, Li Q, et al. Molecular manipulations as tools for enhancing our understanding of 5-HT neurotransmission. Trends Pharmacol Sci. 1999;20:246–252.[Medline] [Order article via Infotrieve]
11.
Nebigil CG, Choi
D-S, Dierich A, et al. Serotonin 2B receptor is required
for heart development. Proc Natl Acad Sci
U S A. 2000;97:9508–9513.
12. Choi D-S, Ward S, Messaddeq N, et al. 5-HT2B receptor-mediated serotonin morphogenetic functions in mouse cranial neural crest and myocardiac cells. Development. 1997;124:1745–1755.[Abstract]
13. Tardiff JC, Factor SM, Tompkins BD, et al. A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. J Clin Invest. 1998;101:2800–2811.[Medline] [Order article via Infotrieve]
14.
Adams JW, Sakata
Y, Davis MG, et al. Enhanced Gq signaling: a common pathway mediates
cardiac hypertrophy and apoptotic heart failure.
Proc Natl Acad Sci
U S A. 1998;95:10140–10145.
15. Collinson PO. Troponin T or troponin I or CK-MB (or none?). Eur Heart J. 1998;19(suppl N):N16–N24.
16. Chien KR, Zhu H, Knowlton KU, et al. Transcriptional regulation during cardiac growth and development. Annu Rev Physiol. 1993;55:77–95.[Medline] [Order article via Infotrieve]
17.
Mann DL, Urabe Y,
Kent RL, et al. Cellular versus myocardial basis for the contractile
dysfunction of hypertrophied myocardium.
Circ Res. 1991;68:402–415.
18.
Schaper J, Froede
R, Hein S, et al. Impairment of the myocardial ultrastructure and
changes of the cytoskeleton in dilated
cardiomyopathy.
Circulation. 1991;83:504–514.
19. McKinsey TA, Olson EN. Cardiac hypertrophy: sorting out the circuitry. Curr Opin Genet Dev. 1999;9:267–274.[Medline] [Order article via Infotrieve]
20. Sussman MA, Welch S, Cambon N, et al. Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice. J Clin Invest. 1998;101:51–61.[Medline] [Order article via Infotrieve]
21.
Emanueli C,
Maestri R, Corradi D, et al. Dilated and failing
cardiomyopathy in bradykinin
B2 receptor knockout mice.
Circulation. 1999;100:2359–2365.
22. Dorn GW II, Brown JH. Gq signaling in cardiac adaptation and maladaptation. Trends Cardiovasc Med. 1999;9:26–34.[Medline] [Order article via Infotrieve]
23. Beltrami CA, Finato N, Rocco M, et al. The cellular basis of dilated cardiomyopathy in humans. J Mol Cell Cardiol. 1995;27:291–305.[Medline] [Order article via Infotrieve]
24. Soler AP, Knudsen KA. N-cadherin involvement in cardiac myocyte interaction and myofibrillogenesis. Dev Biol. 1994;162:9–17.[Medline] [Order article via Infotrieve]
25. Radice GL, Rayburn H, Matsunami H, et al. Developmental defects in mouse embryos lacking N-cadherin. Dev Biol. 1997;181:64–78.[Medline] [Order article via Infotrieve]
26. Wang X, Gerdes AM. Chronic pressure overload cardiac hypertrophy and failure in guinea pigs, III: intercalated disc remodeling. J Mol Cell Cardiol. 1999;31:333–343.[Medline] [Order article via Infotrieve]
27. Goncharova EJ, Kam Z, Geiger B. The involvement of adherens junction components in myofibrillogenesis in cultured cardiac myocytes. Development. 1992;114:173–183.[Abstract]
28. Colas J-F, Launay J-M, Vonesch J-L, et al. Serotonin synchronises convergent extension of ectoderm with morphogenetic gastrulation movements in Drosophila. Mech Dev. 1999;877:77–91.
29. Berul CI, Christe ME, Aronovitz MJ, et al. Familial hypertrophic cardiomyopathy mice display gender differences in electrophysiological abnormalities. J Interv Card Electrophysiol. 1998;2:7–14.[Medline] [Order article via Infotrieve]
30. Towbin JA. The role of cytoskeletal proteins in cardiomyopathies. Curr Opin Cell Biol. 1998;10:131–139. [Medline] [Order article via Infotrieve]
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 B. I. Gustafsson, K. Tommeras, I. Nordrum, J. P. Loennechen, A. Brunsvik, E. Solligard, R. Fossmark, I. Bakke, U. Syversen, and H. Waldum Long-Term Serotonin Administration Induces Heart Valve Disease in Rats Circulation, March 29, 2005; 111(12): 1517 - 1522. [Abstract] [Full Text] [PDF]
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F. Jaffre, J. Callebert, A. Sarre, N. Etienne, C. G. Nebigil, J.-M. Launay, L. Maroteaux, and L. Monassier Involvement of the Serotonin 5-HT2B Receptor in Cardiac Hypertrophy Linked to Sympathetic Stimulation: Control of Interleukin-6, Interleukin-1{beta}, and Tumor Necrosis Factor-{alpha} Cytokine Production by Ventricular Fibroblasts Circulation, August 24, 2004; 110(8): 969 - 974. [Abstract] [Full Text] [PDF]
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J. E. Larkin, B. C. Frank, R. M. Gaspard, I. Duka, H. Gavras, and J. Quackenbush Cardiac transcriptional response to acute and chronic angiotensin II treatments Physiol Genomics, July 8, 2004; 18(2): 152 - 166. [Abstract] [Full Text] [PDF]
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C. Blanpain, E. Le Poul, J. Parma, C. Knoop, M. Detheux, M. Parmentier, G. Vassart, and M. J Abramowicz Serotonin 5-HT2B receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension Cardiovasc Res, December 1, 2003; 60(3): 518 - 528. [Abstract] [Full Text] [PDF]
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 F. Cote, E. Thevenot, C. Fligny, Y. Fromes, M. Darmon, M.-A. Ripoche, E. Bayard, N. Hanoun, F. Saurini, P. Lechat, et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function PNAS, November 11, 2003; 100(23): 13525 - 13530. [Abstract] [Full Text] [PDF]
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C. G. Nebigil and L. Maroteaux Functional Consequence of Serotonin/5-HT2B Receptor Signaling in Heart: Role of Mitochondria in Transition Between Hypertrophy and Heart Failure? Circulation, August 19, 2003; 108(7): 902 - 908. [Full Text] [PDF]
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C. G. Nebigil, F. Jaffre, N. Messaddeq, P. Hickel, L. Monassier, J.-M. Launay, and L. Maroteaux Overexpression of the Serotonin 5-HT2B Receptor in Heart Leads to Abnormal Mitochondrial Function and Cardiac Hypertrophy Circulation, July 1, 2003; 107(25): 3223 - 3229. [Abstract] [Full Text] [PDF]
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 D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
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C. Ozcelik, B. Erdmann, B. Pilz, N. Wettschureck, S. Britsch, N. Hubner, K. R. Chien, C. Birchmeier, and A. N. Garratt Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy PNAS, June 25, 2002; 99(13): 8880 - 8885. [Abstract] [Full Text] [PDF]
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 P. Manivet, B. Schneider, J. C. Smith, D.-S. Choi, L. Maroteaux, O. Kellermann, and J.-M. Launay The Serotonin Binding Site of Human and Murine 5-HT2B Receptors. MOLECULAR MODELING AND SITE-DIRECTED MUTAGENESIS J. Biol. Chem., May 3, 2002; 277(19): 17170 - 17178. [Abstract] [Full Text] [PDF]
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 A. K.L. Banes and S. W. Watts Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension Hypertension, February 1, 2002; 39(2): 394 - 398. [Abstract] [Full Text] [PDF]
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