Abstract 427: Micrornas Have Differential Degree of Expression in Pathological Cardiac Hypertrophy Compared to Physiological Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Nidiane C Martinelli ◽  
Carolina Cohen ◽  
Daiane Silvello ◽  
Andréia Biolo ◽  
Michael Andrades ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Voluntary Exercise ◽  
Expression Levels ◽  
Time Points ◽  
Pathological Cardiac Hypertrophy ◽  
Pathway Activation ◽  
Physiological Cardiac Hypertrophy ◽  
Running Wheels ◽  
Differential Degree

Physiological and pathological left ventricular hypertrophies (LVH) are distinct processes that have differential pattern of gene expression. Based on initial stimuli, miRs expression levels can fluctuate and then cause a variance on their targets culminating in diverse cellular pathway activation. AIM: Here we compared miRs expression between pathological cardiac hypertrophy induced by transverse aortic constriction (TAC) and physiological cardiac hypertrophy induced by voluntary exercise in running wheels (EXE). METHODS: Adult male Balb/c mice (12-14 weeks old) mice were subjected to TAC or EXE protocol and data were evaluated at 7 (TAC-7D; EXE-7D) and 35 (TAC-35D; EXE-35D) days. Hypertrophy was measured by normalizing left ventricular weight to body weight (LVW/BW). We evaluated left ventricular expression levels of miRs: -26b, 27a, -143, -150, -195 and -499 by qRT-PCR in TAC and EXE groups. Comparisons between groups were performed by ANOVA with Bonferroni correction. Results are shown as mean±SEM. Results: Sedentary and Sham groups were similar among all variables tested. Animals subjected to TAC surgery demonstrated a greater hypertrophy than EXE animals at both time points (7D: 16% vs. 7%; 35D 26% vs 12%, p<0.05 for both). MiR-26b had increased levels in TAC group at both time points (7D: 1.14±0.1 vs 0.6±0.01; 35D: 4.8±1.4 vs 1.17±0.12; p<0.01 for both). We only detected an increase in miR-27a levels in TAC-7D compared to EXE-7D (2.7±1.0 vs 0.78±0.1, p <0.05). We identified an augmentation in miR-143 levels in TAC group at both time points (7D: 1.1±0.1 vs 0.75±0.1; 35D: 1.42±0.2 vs 0.9±0.1; p<0.05 for both). We detected an increase in miR-499 levels at both time points in TAC group (7D: 4.1±0.5 vs 0.67±0.2, p<0.001; 35D: 2.2±0.4 vs 0.9±0.2, p<0.01). We found an increase in miR-195 levels only in TAC-35D group compared to EXE-35D (2.6±0.3 vs 0.9±0.1, p<0.05). We did not notice any change in miR-150 levels neither at 7 days nor at 35 days. Conclusions: These preliminary data demonstrate a differential degree of miR expression between physiological and pathological hypertrophy. Further studies comparing physiological and pathological cardiac hypertrophy are necessary to find out the turning point that deviates heart from adaptive to maladaptive growth.

scholarly journals Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat

2001 ◽  
Vol 281 (6) ◽  
pp. R2029-R2036 ◽  
Author(s):  
Motoyuki Iemitsu ◽  
Takashi Miyauchi ◽  
Seiji Maeda ◽  
Satoshi Sakai ◽  
Tsutomu Kobayashi ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Mrna Expression ◽  
Adrenergic Receptor ◽  
Spontaneously Hypertensive Rat ◽  
Left Ventricular ◽  
Control Group ◽  
Trained Group ◽  
Pathological Cardiac Hypertrophy ◽  
Physiological Cardiac Hypertrophy ◽  
Molecular Phenotypes

Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of β1-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of β1-adrenergic receptor kinase mRNA, which inhibits β1-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy.

TGF-β1 and prepro-ANP mRNAs are differentially regulated in exercise-induced cardiac hypertrophy

2001 ◽  
Vol 91 (2) ◽  
pp. 771-776 ◽  
Author(s):  
Angelino Calderone ◽  
René J. L. Murphy ◽  
Julie Lavoie ◽  
Federico Colombo ◽  
Louise Béliveau
Keyword(s):  
Left Ventricle ◽  
Cardiac Hypertrophy ◽  
Transforming Growth Factor ◽  
Mrna Level ◽  
Physiological Model ◽  
Voluntary Exercise ◽  
Sprague Dawley ◽  
Triceps Muscle ◽  
Pathological Cardiac Hypertrophy ◽  
Physiological Cardiac Hypertrophy

The induction of transforming growth factor (TGF)-β and prepro-atrial natriuretic peptide (ANP) mRNAs represent hallmark features of pathological cardiac hypertrophy. The present study examined whether this pattern of mRNA expression was conserved in a physiological model of cardiac hypertrophy. To address this thesis, female Sprague-Dawley rats were individually housed and permitted to run freely. Voluntary exercise for 3 and 6 wk resulted in biventricular hypertrophy and increased cytochrome c oxidase activity in the triceps muscle. In the hypertrophied left ventricle, the steady-state mRNA level of the cardiac fetal gene prepro-ANP and the extracellular matrix proteins preprocollagen-α1 and fibronectin were similar in exercise-trained and sedentary rats. By contrast, an increased expression of TGF-β1 mRNA was observed, whereas TGF-β3 mRNA level was unchanged in the hypertrophied left ventricle of exercise-trained compared with sedentary rats. These data highlight a heterogeneity in the regulation of TGF-β isoforms, and the increased expression of ventricular TGF-β1 mRNA in physiological cardiac hypertrophy may contribute to myocardial remodeling.

P1606Glutamine-fructose-6-phosphate amidotransferase 2 mediates isoproterenol-induced cardiac hypertrophy by increasing Akt O-GlcNAcylation through hexosamine biosynthesis pathway

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Ishikita ◽  
S Matsushima ◽  
S Ikeda ◽  
K Okabe ◽  
T Tadokoro ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Biosynthesis Pathway ◽  
Post Translational Modification ◽  
Expression Levels ◽  
Pathological Cardiac Hypertrophy ◽  
Hexosamine Biosynthesis ◽  
Hexosamine Biosynthesis Pathway

Abstract Background Cardiac hypertrophy is an independent risk factor for heart failure and cardiac death. Hexosamine biosynthesis pathway (HBP), an accessory pathways of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. However, the role of HBP has not been determined in pathological cardiac hypertrophy. Purpose The purpose of this study to examine whether glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical enzyme of HBP, mediates cardiac hypertrophy by protein O-GlcNAcylation and activating hypertrophic signaling in cardiomyocytes. Methods and results C57BL/6J mice were treated with isoproterenol (ISO: 15 mg/kg/day, 1 week) with or without 6-Diazo-5-oxo-L-norleucine (DON, an inhibitor of GFAT: 500 μg/kg/day, 1week). ISO-treated mice (ISO+vehicle) showed cardiac hypertrophy, which were attenuated in ISO and DON-treated mice (ISO+DON) (heart weight to tibial length ratio: 7.70±0.09 vs. 7.11±0.15 mg/mm, n=12, p<0.05, left ventricular wall thickness: 1.05±0.02 vs. 0.86±0.03 mm, n=6, p<0.05). Cardiomyocyte cross-sectional area was also decreased in ISO+DON compared with ISO+vehicle (309±25 vs. 252±13 mm2, n=,3 p<0.05). Whereas expression levels of GFAT2 and protein O-GlcNAcylation in the heart were increased in ISO+vehicle compared with control+vehicle by 3.3 and 1.5 folds, respectively (n=9 and n=9, p<0.05), expression levels of O-GlcNAc transferase (OGT) and the β-N-acetylglucosaminidase (OGA), other enzymes regulating O-GlcNAcylation, were not altered in both groups, indicating that ISO activated HBP by GFAT2. Protein O-GlcNAcylation in ISO+DON was lower than that in ISO+vehicle by 83% (n=9, p<0.05). In addition, phosphorylation of Akt, a critical mediator of cardiac hypertrophy, but not other mediators of cardiac hypertrophy such as ERK, JNK, or p38MAPK, was significantly decreased in ISO+DON by 76% (n=9, p<0.05). In cultured neonatal rat ventricular myocytes, treatment with ISO (1μM, 12h) increased the expression levels of GFAT2 and protein O-GlcNAcylation by 1.3 and 1.5 folds, respectively (n=6 and n=6, p<0.05), but not GFAT1. Furthermore, ISO stimulation increased a direct O-GlcNAcylation of Akt by 1.4 folds (n=3, p<0.05). Downregulation of GFAT2 by RNA silencing decreased cell size by 82% (n=6, p<0.05) and protein O-GlcNAcylation and phosphorylation of Akt by 76% and 54%, respectively (n=9 and n=9, p<0.05) in cardiomyocyte treated with ISO. Conversely, administration of glucosamine, a substrate of HBP, increased protein of O-GlcNAcylation and phosphorylation of Akt by 1.3 and 1.8 folds, respectively (n=6 and n=6, p<0.05). Conclusions GFAT2, a limiting enzyme of HBP, mediates pathological cardiac hypertrophy by Akt activation probably due to its O-GlcNAcylation. GFAT2-O-GlcNAcylation-Akt pathway might be a potential novel therapeutic target for cardiac hypertrophy.

Abstract 16165: Inorganic Arsenic Induces Sex-Dependent Pathological Cardiac Hypertrophy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Raihan Kabir ◽  
Prithvi Sinha ◽  
Sumita Mishra ◽  
Obialunanma V Ebenebe ◽  
Nicole Taube ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Inorganic Arsenic ◽  
Left Ventricular ◽  
Luciferase Assay ◽  
Heart Weight ◽  
Left Ventricular Geometry ◽  
Wall Thickening ◽  
Pathological Cardiac Hypertrophy ◽  
Relevant Dose

Exposure to inorganic arsenic (iAS) through drinking water is well-associated with adverse cardiovascular outcomes, yet the mechanisms through which it induces these effects are not fully understood. Recent epidemiological findings highlight an association between iAS exposure and altered left ventricular geometry in both the presence and absence of hypertension. We therefore tested the hypothesis that iAS exposure has a bimodal impact on cardiac-intrinsic and hemodynamic mechanisms that together induce pathological remodeling of the myocardium. Adult male and female mice were exposed to an environmentally relevant dose of 615 μg/L NaAsO 2 for eight weeks. Males (n=9-10 mice/group) exhibited increased systolic blood pressure (115.1±3.0 vs. 106.0±2.3 mmHg, p=0.0350) via tail cuff photoplethysmography, left ventricular wall thickening (0.98±0.01 vs. 0.88±0.01 mm, p<0.0001) via transthoracic echocardiography, increased heart weight to tibia length (8.56±0.21 vs. 7.15±0.24 mg/mm; n=24 mice/group), and increased plasma atrial natriuretic peptide (47.85±12.0 vs. 15.14±3.73 pg/mL, p=0.0379) via enzyme immunoassay. Myocardial mRNA transcript levels (n=10 hearts/group) of Acta1 (1.36±0.18 vs. 0.73±0.11, p=0.0037), Myh7 (1.53±0.15 vs. 1.04±0.10, p=0.0138), and Nppa (2.40±0.29 vs. 1.02±0.07, p=0.0001) were increased, and Myh6 (0.92±0.17 vs. 1.14±0.23, p=0.0001) was decreased, evidencing pathological hypertrophy in the male heart. Female hearts, however, were largely protected at this eight-week timepoint as similar changes were not detected. Further investigation found that Rcan1 was upregulated (1.47±0.19 vs. 0.97±0.04, p=0.0161; n=10 hearts/group) in male hearts, suggesting that calcineurin-NFAT was activated. Interestingly, iAS was sufficient to activate NFAT (0.82±0.11 vs. 0.46±0.05, p=0.0214; n=8 wells/group) independent of blood pressure via luciferase assay. In conclusion, these results demonstrate for the first time that iAS may cause pathological cardiac hypertrophy not only by increasing hemodynamic load, but also by activating calcineurin-NFAT and inducing fetal gene expression in the male heart, thus providing novel mechanistic insight into the threat of iAS exposure to the cardiovascular system.

scholarly journals Muscle ring finger 1 mediates cardiac atrophy in vivo

2009 ◽  
Vol 296 (4) ◽  
pp. H997-H1006 ◽  
Author(s):  
Monte S. Willis ◽  
Mauricio Rojas ◽  
Luge Li ◽  
Craig H. Selzman ◽  
Ru-Hang Tang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Transcriptional Activation ◽  
Smooth Muscle Actin ◽  
Ring Finger ◽  
Left Ventricular ◽  
Cardiac Mass ◽  
Wild Type ◽  
Cardiac Atrophy ◽  
Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1−/− mice decreased ∼70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by β-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1−/− and wild-type hearts after TAC release. In the second model, MuRF1−/− mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic regression of cardiac hypertrophy and dexamethasone-induced atrophy.

scholarly journals Supra-physiological dose of testosterone induces pathological cardiac hypertrophy

2016 ◽  
Vol 229 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Prapawadee Pirompol ◽  
Vassana Teekabut ◽  
Wattana Weerachatyanukul ◽  
Tepmanas Bupha-Intr ◽  
Jonggonnee Wattanapermpool
Keyword(s):  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Male Rats ◽  
Cross Sectional ◽  
Physiological Level ◽  
Testosterone Treatment ◽  
Pathological Cardiac Hypertrophy ◽  
Physiological Cardiac Hypertrophy ◽  
Hypertrophy Of The Heart ◽  
Contractile Activation

Testosterone and androgenic anabolic steroids have been misused for enhancement of physical performance despite many reports on cardiac sudden death. Although physiological level of testosterone provided many regulatory benefits to human health, including the cardiovascular function, supra-physiological levels of the hormone induce hypertrophy of the heart with unclear contractile activation. In this study, dose- and time-dependent effects of high-testosterone treatment on cardiac structure and function were evaluated. Adult male rats were divided into four groups of testosterone treatment for 0, 5, 10, and 20 mg/kg BW for 4, 8, or 12 weeks. Increases in both percentage heart:body weight ratio and cardiomyocyte cross-sectional area in representing hypertrophy of the heart were significantly shown in all testosterone-treated groups to the same degree. In 4-week-treated rats, physiological cardiac hypertrophy was apparent with an upregulation of α-MHC without any change in myofilament contractile activation. In contrast, pathological cardiac hypertrophy was observed in 8- and 12-week testosterone-treated groups, as indicated by suppression of myofilament activation and myocardial collagen deposition without transition of MHC isoforms. Only in 12-week testosterone-treated group, eccentric cardiac hypertrophy was demonstrated with unaltered myocardial stiffness, but significant reductions in the phosphorylation signals of ERK1/2 and mTOR. Results of our study suggest that the outcome of testosterone-induced cardiac hypertrophy is not dose dependent but is rather relied on the factor of exposure to duration in inducing maladaptive responses of the heart.

scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

Inhibition of angiotensin II-induced hypertrophy and cardiac dysfunction by North American ginseng (Panax quinquefolius)

2020 ◽  
Author(s):  
Xilan Tang ◽  
Tracey Gan ◽  
Chian Ju Jong ◽  
Venkatesh Rajapurohitam ◽  
Morris Karmazyn
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
North American ◽  
Glucose Oxidation ◽  
American Ginseng ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Expression Levels

We determined whether North American ginseng mitigates the effect of angiotensin II on hypertrophy and heart failure. Angiotensin II (0.3 mg/kg) was administered to rats for 2 or 4 weeks in the presence or absence of ginseng pretreatment. The effect of ginseng (10 μg/mL) on angiotensin II (100 nM) induced hypertrophy was also determined in neonatal rat ventricular myocytes. We also determined effects of ginseng on fatty acid and glucose oxidation by measuring gene and protein expression levels of key factors. Angiotensin II treatment for 2 and 4 weeks induced cardiac hypertrophy as evidenced by increased heart weights as well as the upregulation of the hypertrophy-related fetal gene expression levels with all effects being abolished by ginseng. Ginseng also reduced abnormalities in left ventricular function as well as the angiotensin-induced increased blood pressure. In myocytes, ginseng abolished the hypertrophic response to angiotensin II as assessed by surface area and gene expression of molecular markers of hypertrophy. Ginseng modulated angiotensin II-induced abnormalities in gene expression and protein levels of CD36, CPT1M, Glut4 and PDK4 in vivo and in vitro. In conclusion, ginseng suppresses angiotensin II induced cardiac hypertrophy and dysfunction which is related to normalization of fatty acid and glucose oxidation.

Abstract 119: Targeting Cardiac Hypertrophy with Small Molecule Inhibitors of JMJD2A

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Qing-jun Zhang ◽  
Ganesha Rai ◽  
Ajit Jadhav ◽  
Anton Simeonov ◽  
David Maloney ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Enzymatic Activity ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Epigenetic Modification ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Innovative Drug ◽  
Pathological Cardiac Hypertrophy

One of the major challenges in managing and treating heart failure patients is to develop disease-modifying drugs that can prevent, reverse, or slow down the disease progression. Upon pathological insults, the heart undergoes remodeling processes, including left ventricular hypertrophy and reprogramming of gene expression. Understanding the mechanisms involved could provide a key to develop interventional therapeutics. Epigenetic modification of chromatin, including histone methylation, regulates gene transcription in response to environmental signals. JMJD2A is a trimethyl-lysine specific histone lysine demethylase. To study the role of JMJD2A, we generated heart specific JMJD2A overexpression and deletion mouse lines. Our studies with these genetically modified mice indicated that JMJD2A is required for pathological cardiac hypertrophy. Furthermore, we show that the demethylase activity of JMJD2A is required for its transcriptional activity. These data suggests that targeting JMJD2A enzymatic activity may be used to suppress hypertrophic remodeling. To test this hypothesis, we tested a collection of small molecule inhibitors of JMJD2 in collaboration with Chemists in NIH and identified several small molecule inhibitors of JMJD2A that are active in cell-based assays. These small molecule inhibitors of JMJD2A inhibited the phenylephrine-stimulated cardiomyocyte hypertrophy in vitro. Our data suggests that JMJD2A enzymatic activity may act as a hypertrophic determinant and may be an innovative drug target for prevention and treatment of pathological cardiac hypertrophy and heart failure.

scholarly journals Thyroid Hormone-Induced Cardiac Mechano Growth Factor Expression Depends on Beating Activity

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 830-838 ◽  
Author(s):  
Miriam van Dijk-Ottens ◽  
Ingrid H. C. Vos ◽  
Peter W. A. Cornelissen ◽  
Alain de Bruin ◽  
Maria E. Everts
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Thyroid Hormone ◽  
Cardiac Hypertrophy ◽  
Mrna Expression ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Mechano Growth Factor ◽  
Physiological Cardiac Hypertrophy

The mechano growth factor (MGF), a splice variant of the IGF-I gene, was first discovered in mechanically overloaded skeletal muscle and was shown to play an important role in proliferation of muscle stem cells. Since then, the presence and effects of MGF have been demonstrated in other tissues. MGF has been shown to act neuroprotectively during brain ischemia, and pretreatment with MGF before myocardial infarction improves cardiac function. Because MGF plays a permissive role in exercise-induced skeletal muscle hypertrophy, we hypothesize that MGF is commonly involved in cardiac hypertrophy. To investigate the regulation of MGF expression in heart, mice were treated with thyroid hormone (T3) for 12 d to induce physiological cardiac hypertrophy. MGF mRNA expression was specifically increased in midregions of the septum and left ventricular wall. Interestingly, MGF expression strongly correlated with the increased or decreased beating frequency of hyperthyroid and hypothyroid hearts. To further investigate the mechanically dependent induction of MGF, neonatal rat cardiomyocytes were isolated and exposed to T3. Upon T3 treatment, cardiomyocytes increased both contractile activity measured as beats per minute and MGF as well as IGF-IEa mRNA expression. Importantly, when cardiomyocytes were contractile arrested by KCl, simultaneous exposure to T3 prevented the up-regulation of MGF, whereas IGF-IEa was still induced. These studies demonstrated that MGF but not IGF-IEa expression is dependent on beating activity. These findings suggest that MGF is specifically stimulated by mechanical loading of the heart to mediate the hypertrophic response to thyroid hormone.

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