Published online before print June 16, 2003, doi: 10.1161/01.CIR.0000074224.57016.01
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(Circulation. 2003;107:3223.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Overexpression of the Serotonin 5-HT2B Receptor in Heart Leads to Abnormal Mitochondrial Function and Cardiac Hypertrophy
From Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch, France (C.G.N., F.J, N.M., L. Maroteaux); Laboratoire de Neurobiologie et de Pharmacologie Cardiovasculaire, Faculté de Médecine, Strasbourg, France (L. Monassier); and Centre de Recherches Claude Bernard, Service de Biochimie, Hôpital Lariboisière, Paris, France (J.M.L.).
Correspondence to L. Maroteaux, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, BP 10142-67404 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. We previously reported that 5-HT2B receptor ablation in mice leads to dilated cardiomyopathy. In this study, we investigated the pathological consequence of overexpressing 5-HT2B receptors in heart in vivo.
Methods and Results— We have generated transgenic mice overexpressing the Gq-coupled 5-HT2B receptor specifically in heart. We found that overexpression of 5-HT2B receptor in heart leads to ventricular hypertrophy as the result of increased cell number and size. Increased atrial natriuretic peptide and myosin heavy chain expression demonstrated activation of the molecular program for cardiac hypertrophy. Echocardiographic analysis indicated the presence of thickened ventricular free wall without alteration of the systolic function, showing that transgenic mice have compensated hypertrophy. Electron microscopic analysis revealed structural abnormalities including mitochondrial proliferation, as also manifested by histological staining. Transgenic mouse heart displayed a specific reduction in the expression levels of the adenine nucleotide translocator associated to increase in the succinate dehydrogenase and cytochrome C oxidase mitochondrial activities.
Conclusions— Our results constitute the first genetic evidence that overexpression of the 5-HT2B receptor in the heart leads to compensated hypertrophic cardiomyopathy associated with proliferation of the mitochondria. This observation suggests a role for mitochondria in the hypertrophic signaling that is regulated by serotonin. These transgenic mice provide a new genetic model for hypertrophic heart disease.
Key Words: cardiomyopathy • genetics • hypertrophy • receptors • signal transduction
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Introduction |
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Cardiac hypertrophy is characterized by increased ventricular wall thickness and occurs in 1 of 500 healthy young individuals.1 Hypertrophy is a compensatory physiological response to excessive hemodynamic burden or a pathological state. Pathological hypertrophy initially occurs to compensate altered hemodynamic demands on the failing myocardium and is mediated by systemic and/or local upregulators such as adrenergic, endothelin, or renin-angiotensin axes and by various cytokines. The first group of myocardial receptors, ß-adrenergic receptors, which couple primarily to Gs, mediates acute enhancement of heart rate and myocardium contractility in response to stimulation. The second class of myocardial receptors is the cholinergic receptors, typically coupled to Gi. The third class of receptors, coupled primarily to Gq, includes angiotensin II, endothelin, and
-adrenergic receptors.2 Activation of this last pathway is less important in modulating minute-by-minute cardiac function, but it is likely to play a major role in cardiac hypertrophic responses to pathological stimuli. Overexpression of Gq-coupled receptors contributes to the development and ultimate decompensation of cardiac hypertrophy as the result of extensive apoptosis.2–5 Two phases of Gq-stimulated cardiac hypertrophy are observed in transgenic (TG) mouse models: Moderate levels of Gq signaling produce cardiac hypertrophy, whereas high levels result in cardiomyocyte apoptosis.6,7 Recently, the complete absence of hypertrophic response in Gq/G11-ablated mouse heart indicated that both Gq- and G11-mediated phospholipase C activation represent essential pathways.5
Serotonin (5-hydroxytryptamine, 5-HT) as a neurohormone regulates cardiovascular functions during embryogenesis and adulthood. 5-HT is secreted from enterochromaffin cells into the blood and stored in the platelets. Circulating 5-HT can also be taken up by sympathetic neurons and vascular endothelial cells and can be coreleased.8 The Gq-coupled 5-HT2B receptor (5-HT2BR) belongs to one of the four classes of 5-HT receptors (5-HT1/5, 5-HT2, 5-HT3, and 5-HT4/6/7).9 Genetic ablation of 5-HT2BR in mice leads to partial embryonic and neonatal death as the result of the following heart defects: (1) 5-HT2BR mutant embryos exhibit a lack of trabeculae in the heart, leading to mid-gestation lethality.10 (2) In newborn mice, contractility and structural deficits at cellular junctions in 5-HT2BR mutant cardiomyocytes lead to cardiac dilation. (3) In the adult 5-HT2BR mutant mice, echocardiography and electrocardiography both confirm the presence of left ventricular dilation and decreased systolic function typical of dilated cardiomyopathy.11 These results constituted the first genetic evidence that 5-HT through 5-HT2BR can regulate differentiation and proliferation of developing heart and structure and function of adult heart.
Although 5-HT2BR ablation (loss of function) in mice leads to dilated cardiomyopathy, the consequence of overexpression of Gq-coupled 5-HT2BR (gain of function) in heart remains undefined. In this study, we used an in vivo approach by developing TG mice overexpressing 5-HT2BR in heart to further investigate the pathophysiological role of 5-HT through 5-HT2BR.
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Methods |
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Generation of TG Mice
A 5.5-kilobasepair (Kbp) BamHI-KpnI restriction fragment of the mouse
-myosin heavy chain (MHC) was fused to a 2.0-Kbp XbaI-XbaI restriction fragment of mouse 5-HT2BR cDNA. The recombinant plasmid p-MHC-5-HT2B was linearized, microinjected into pronuclei of fertilized CD1 mouse eggs, and implanted into pseudopregnant CD1 foster mothers. Mouse tail DNA hybridized with the 5-HT2BR cDNA labeled with [32P] dATP was used to ascertain gene transfer. All animal experimentation was performed in accordance with institutional guidelines and the French Animal Care Committee, with European regulation–approved protocols.
Analysis of Mouse 5-HT2BR Expression
Membrane proteins prepared from 6-week-old mouse heart ventricles were analyzed by binding studies with specific tritiated antagonists of the 5-HT2B (3H-LY266070) or 5-HT2A (3H-MDL100907) receptors, as previously described.10
Echocardiography Methods
Animals were weighed and analyzed for cardiac anatomy and function on a Sonos 5500 (Philips Electronics, Koninklijke, the Netherlands) with a 15-MHz linear transducer (15L6), as previously described.11 All the examinations were performed in mice anesthetized with sodium pentobarbital (30 mg/kg IP). All the measurements were performed according to the guidelines of the American Society of Echocardiography.
Blood Pressure Measurements
Systolic arterial pressure and heart rate were recorded by the tail-cuff technique in awake mice, as previously described.11
Morphological Analysis of Mouse Heart
Transmission electron microscopy (TEM) and histological techniques were performed as previously described.10 Hearts were dissected, fixed, paraffin-embedded, and sectioned (7 µmol/L) on a microtome, using standard techniques. Ragged-red fibers (RRF) were revealed by staining the sections using the trichrome of Gomori’s technique.12
Western Blot Analysis
For Western blots, 
20 µg of heart protein was separated on 10% SDS/PAGE and blotted to nitrocellulose membranes. To verify loading homogeneity, the same blots were stripped and reprobed with an antibody against ß-actin. Blots were stripped with 6.25 mmol/L Tris pH 7.5, 2% SDS, and 100 mmol/L 2-mercaptoethanol for 30 minutes at 45°C and washed for1 hour. Antibody-antigen complexes were detected with an ECL kit according to manufacturer instructions. We used the following antibodies: 5-HT2BR (Pharmingen, San Diego, Calif), MHC MF-20 (Hybridoma bank, Iowa City, Iowa), atrial natriuretic factor (ANF) (Amersham Biosciences, Orsay, France), adenine nucleotide translocator (ANT) (Santa Cruz Biotech, Santa Cruz, Calif), ß-actin (Sigma-Aldrich, Lyon, France), and voltage-dependent anion channel (VDAC) (Santa Cruz Biotech). The ECL signals were quantified through the use of an image analyzer (GS-700, Bio-Rad, Hercules, Calif) and calculated as arbitrary units.
Analysis of Hypertrophic Cardiac Genes by RT-PCR
Semi-quantitative RT-PCR was performed on 1 µg of total RNA extracted from age-matched control and knockout mice, using the ribosomal elongation factor 1A as an internal control as previously described.10 The following primers were used: for ANF 5'-ccaggccatattggagcaaa and 5'-gaagctgttgcagcctagtc; for -MHC 5'-ctgctggagaggttattcctcg and 5'-ggaagagtgagcggcgcatcaagg; for ß-MHC 5'-tgcaaaggctccaggtctgagggc and 5'-gccaacaccaccctgtccaagttc; for desmin 5'-tgatgaggcagatgagggag and 5'-tgaga-gctgagaaggtctgg.
Enzyme Activity and Histochemistry
The histochemical enzyme analysis of succinate dehydrogenase (SDH) and cytochrome C oxidase (COX) activities were performed on cryosections of unfixed heart as described13 and on heart whole-cell extract as described.14
Cardiomyocyte Morphology Determination and Microscopic Analysis
Immunohistochemistry was performed on heart cryosections with the antisarcomeric MHC MF-30 (Hybridoma Bank), ANF, or ANT antibody as described.10 Confocal microscope images were used to evaluate the total number of MHC-positive cells. The percentage of cardiomyocytes in a given field was calculated by determining the number of cardiomyocytes that showed green cytoplasmic MHC staining and dividing by the total number of cells in the field, which were visualized by red nuclear propidium iodide (PI) staining. Isolated cardiomyocyte size was determined as described.10,15
Data Analysis and Statistics
All values represent the average values of independent experiments (±SEM, n=number of experiments as indicated in the text). Comparisons between groups were performed by using the Student’s unpaired t test or ANOVA and a Fisher’s test. Significance was set at a value of P<0.05.
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Results |
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Generation of TG Mice
We used a cardiomyocyte-specific promoter to generate TG mice to determine the consequence of abnormal expression of 5-HT2BR in heart. The transgene consisted of the cardiomyocyte-specific
-MHC promoter16 linked to the entire coding sequence for the mouse 5-HT2BR (Figure 1A). A TG founder mouse was obtained that successfully transmitted the transgene to its progeny (Figure 1B). TG mice were recovered at mendelian frequency and survived to adulthood. Immunoblot analysis performed with a 5-HT2BR antibody showed that the 5-HT2BR protein level was increased in heart lysate of TG compared with nontransgenic (NTG) mice (Figure 1C). Binding assay with a 5-HT2BR–specific–labeled compound revealed 6.8-fold overexpression of 5-HT2BR but no significant changes in 5-HT2AR protein in the heart (Figure 1C). These data show a specific 5-HT2BR overexpression in the TG heart.
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Heart Morphology and Cardiac Functions
Cardiac functions and anatomy were assessed in 12-week-old male mice. Histological analysis revealed an increase in the thickness of the left ventricular free wall from TG mice (Figure 2). Echocardiographic analysis confirmed that the posterior wall thickness (28±5%) and the total left ventricular mass (22.8±8.8%) were significantly increased in adult TG mice. TG mice also showed increased left ventricle weight–to–body weight ratio by 178%. Left ventricular end-systolic or end-diastolic diameters, fractional shortening, or systolic blood pressure was not altered, whereas heart rate was slightly increased in the TG mice. No loss of systolic performance occurred in the TG mice, indicating a compensated hypertrophy (Table).
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Cardiomyocyte Number and Size
We next investigated the mechanism leading to the increased ventricular mass found in 5-HT2BR TG heart. Total cell and cardiomyocyte numbers were determined from frozen sections stained with PI and cardiomyocyte-specific MHC antibody, respectively. As shown in Figure 3, heart from TG had 11.0±0.4% more cardiomyocytes than from NTG mice. Isolated TG cardiomyocytes had a significant increase in size by 23±5%. These data indicate that the increase in ventricular mass observed in TG mice results from increases in both cell density and size of cardiomyocytes.
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Hypertrophic Gene Expression in Heart
To determine whether the hypertrophic growth is associated with altered expression of hypertrophic markers,17 expression was evaluated in adult TG heart. Semiquantitative RT-PCR analysis of TG heart mRNA demonstrated an increase in ANF expression and ß-MHC and no change in -MHC or desmin levels. Western blot analysis confirmed the increase in ANF expression by 40% and MHC by 70% (Figure 4A) as well as immunohistochemical staining on the cryosectioned heart (Figure 4B). These changes in expression demonstrate the activation of a molecular program for cardiac hypertrophy in TG heart.
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Heart Ultrastructural Analysis
Ultrastructural study by TEM revealed structural abnormalities along with mitochondrial proliferation in TG mice ventricular myocardium compared with NTG. Moreover, TG heart exhibited lipid deposition and T-tubules enlargement (Figure 5, A and B). The sarcomere structure of TG appeared normal, but mitochondria were rounded, irregular, and higher in number. Notably, no evidence for myocardial apoptosis, fibrosis, or significant inflammatory cell infiltrates was found.
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Heart Mitochondrial Function
To verify mitochondrial proliferation, we stained cryosections of the heart with the modified Gomori’s trichrome stain that reveals red staining material associated with proliferation of mitochondria (RRF).12 TG mice heart demonstrated typical RRF staining that was not observed in the NTG mouse heart (Figure 6A). To investigate the mitochondrial function, enzymatic activities for COX and SDH were measured. Activity assay on whole-heart extract showed a significantly increased activity of both SDH and COX in the TG compared with NTG. Enzymatic histochemical staining for SDH and COX activity confirmed the increased activity of both SDH and COX by 54.0±0.5% and 28.8±4.0%, respectively, in the TG heart (Figure 6A).
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It has previously been reported that the expression of ANT was increased in association with mitochondrial defects.18 Western blot analysis on total heart lysate showed a decreased ANT protein expression by 32% in the TG mice without alterations in the VDAC levels, which was confirmed by immunostaining of heart cryosections (Figure 6B). Together, these data indicate increased respiratory chain and oxidative phosphorylation in the mitochondria of TG heart that are associated with 5-HT2BR overexpression.
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Discussion |
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Our previous study has shown that loss of function for the Gq-coupled 5-HT2BR leads to dilated cardiomyopathy.11 In this study, we used a TG animal model overexpressing the 5-HT2BR in heart to provide novel insights in the determinants for cardiomyocyte growth in response to 5-HT. Overexpression of 5-HT2BR in heart leads to cardiac hypertrophy accompanied by abnormal mitochondrial proliferation and enzyme activity, indicating an essential role for 5-HT in the hypertrophic signaling.
TG mice have heart hypertrophy as the result of an increased number of cardiomyocytes and increased growth. The overexpression of 5-HT2BR raises the expression of hypertrophic genes such as ANF and ß-MHC as an evidence of hypertrophic response in the TG heart. This response should be a direct effect of 5-HT2BR overexpression because hypertrophy was observed without evidence of hemodynamic overload. Cardiac fibrosis was not observed in TG mouse heart, indicating that myocardial overexpression of 5-HT2BR did not alter remodeling in noncardiomyocyte cells through paracrine mechanisms.
The involvement of the Gq-coupled receptor in regulating cardiomyocyte hypertrophy is not yet fully understood despite the use of both loss and gain of function to study the same receptor in vivo. For example, cardiac hypertrophy develops in TG mice overexpressing angiotensin AT1 receptors in the myocardium,19 but pressure overload and stretch-induced hypertrophy still occur in AT1 knockout mice.20 Our previous work showed that ablation of Gq-coupled 5-HT2BR in mice leads to dilated cardiomyopathy without hypertrophic response, and the current study shows that overexpression of this receptor leads to a compensated cardiac hypertrophy.
Several factors might be responsible for the development of compensatory hypertrophy after 5-HT2BR overexpression. A first possibility is a change in signaling pathways and Gq-protein repertoire coupling. In TG mice, cardiac-specific overexpression of constitutively active 
-PKC and 
-PKC isoforms caused identical nonpathological cardiac hypertrophy.21,22 TG mice with cardiac-restricted expression of an activated MEK1 had concentric hypertrophy without signs of cardiomyopathy or lethality, indicating a hypertrophic response associated with augmented cardiac function and partial resistance to apoptosis.23 Overexpression may modify the coupling of 5-HT2BRs that can activate p60Src and MAPK pathways,24,25 phospholipase C and A2,26 and nitric oxide synthesis.27,28
A second possible cause of hypertrophy after overexpression of 5-HT2BR is an altered proliferation/survival of cardiomyocytes. Recently, we have shown that activation of 5-HT2BR inhibits apoptosis induced by serum withdrawal in isolated cardiomyocytes.29 Moreover, 5-HT2BR knockout newborn mice have ventricular hypoplasia as the result of impaired proliferation of cardiomyocytes.10 It is possible that overexpression of 5-HT2BR in heart activates the mitogenic pathway before birth and then inhibits apoptosis, because cardiomyocytes became terminally differentiated and nonproliferative shortly after the birth. Overexpression of this receptor in the 5-HT2BR TG mouse heart leads to hypertrophy associated with mitochondrial proliferation and increased mitochondrial enzyme activity such as COX and SDH.
The role of mitochondria in transition from compensatory hypertrophy to maladaptation has not been clearly elucidated. It is likely that mitochondrial functional changes are associated with compensatory hypertrophy (adaptative response). However, failing mitochondrial functions occur with heart failure (decompensation) and induction of apoptotic signaling. To modify or abort decompensation, intrinsic determinants of mitochondrial apoptosis have recently been elucidated. Nix/Bnip3L, a critical component of the apoptotic program for Gq-mediated apoptosis of cardiomyocytes, is upregulated in cardiac hypertrophy induced by the Gq pathway30 without a generalized increase in apoptotic mediators.
5-HT2BR knockout mice heart has an increased expression of the ANT that is regulated by 5-HT in isolated cardiomyocytes through PI3K/Akt/NF-
B signaling.29 ANT, the only mitochondrial carrier for ADP and ATP, combines mitochondrial energy-producing and cytosolic energy-consuming processes. In heart tissue from patients with dilated cardiomyopathy, an increase in the ANT mRNA was found,31,32 and point mutations in the ANT gene have been reported in humans to generate genetic mitochondrial disease.33 ANT overexpression leads to the phenotypical alteration of the apoptosis, that is, collapsed mitochondrial membrane potential, cytochrome C release, caspase activation, and DNA degradation.34 Interestingly, histological and ultrastructural examination of muscle from ANT null mutant mice revealed RRF, COX, and SDH activation, cardiac hypertrophy with mitochondria proliferation.35 Here, a similar phenotype is observed with ANT downregulation in the heart of 5-HT2BR–overexpressing TG mice. In cardiomyocytes, ANT may thus regulate functions of mitochondria, which are important cellular components that act at hypertrophy or decompensation. In conclusion, our findings show that overexpression of 5-HT2BR leads to hypertrophic cardiomyopathy and is associated with altered mitochondrial function.
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Acknowledgments |
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This work was supported by funds from the Center 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, and from the Association pour la Recherche contre le Cancer. Dr Nebigil is supported by a fellowship from the Lefoulon-Delalande Fondation.
Received January 13, 2003; revision received March 14, 2003; accepted March 17, 2003.
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P. Bianchi, O. Kunduzova, E. Masini, C. Cambon, D. Bani, L. Raimondi, M.-H. Seguelas, S. Nistri, W. Colucci, N. Leducq, et al. Oxidative Stress by Monoamine Oxidase Mediates Receptor-Independent Cardiomyocyte Apoptosis by Serotonin and Postischemic Myocardial Injury Circulation, November 22, 2005; 112(21): 3297 - 3305. [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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