scholarly journals Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4

2006 ◽  
Vol 290 (5) ◽  
pp. H1997-H2006 ◽  
Author(s):  
Fan Xiang ◽  
Yasuhiko Sakata ◽  
Lei Cui ◽  
Joey M. Youngblood ◽  
Hironori Nakagami ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Marker Genes ◽  
Recognition Sequence ◽  
Inhibitory Interaction ◽  
Hypertrophic Response ◽  
Neonatal Cardiomyocytes

Pathological cardiac hypertrophy is considered a precursor to clinical heart failure. Understanding the transcriptional regulators that suppress the hypertrophic response may have profound implications for the treatment of heart disease. We report the generation of transgenic mice that overexpress the transcription factor CHF1/Hey2 in the myocardium. In response to the α-adrenergic agonist phenylephrine, they show marked attenuation in the hypertrophic response compared with wild-type controls, even though blood pressure is similar in both groups. Isolated myocytes from transgenic mice demonstrate a similar resistance to phenylephrine-induced hypertrophy in vitro, providing further evidence that the protective effect of CHF1/Hey2 is mediated at the myocyte level. Induction of the hypertrophy marker genes ANF, BNP, and β- MHC in the transgenic cells is concurrently suppressed in vivo and in vitro, demonstrating that the induction of hypertrophy-associated genes is repressed by CHF1/Hey2. Transfection of CHF1/Hey2 into neonatal cardiomyocytes suppresses activation of an ANF reporter plasmid by the transcription factor GATA4, which has previously been shown to activate a hypertrophic transcriptional program. Furthermore, CHF1/Hey2 binds GATA4 directly in coimmunoprecipitation assays and inhibits the binding of GATA4 to its recognition sequence within the ANF promoter. Our findings demonstrate that CHF1/Hey2 functions as an antihypertrophic gene, possibly through inhibition of a GATA4-dependent hypertrophic program.

scholarly journals Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

2004 ◽  
Vol 279 (19) ◽  
pp. 20422-20434 ◽  
Author(s):  
Sagartirtha Sarkar ◽  
Douglas W. Leaman ◽  
Sudhiranjan Gupta ◽  
Parames Sil ◽  
David Young ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Gene Clusters ◽  
The United States ◽  
Cellular Interaction ◽  
Marker Genes ◽  
Human Heart Failure

Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Many studies have suggested that, under stress, myocardium releases factors triggering protein synthesis and stimulating myocyte growth. We identified and cloned myotrophin, a 12-kDa protein from hypertrophied human and rat hearts. Myotrophin (whose gene is localized on human chromosome 7q33) stimulates myocyte growth and participates in cellular interaction that initiates cardiac hypertrophyin vitro. In this report, we present data on the pathophysiological significance of myotrophinin vivo, showing the effects of overexpression of cardio-specific myotrophin in transgenic mice in which cardiac hypertrophy occurred by 4 weeks of age and progressed to heart failure by 9-12 months. This hypertrophy was associated with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines, with symptoms that mimicked those of human cardiomyopathy, functionally and morphologically. This model provided a unique opportunity to analyze gene clusters that are differentially up-regulated during initiation of hypertrophyversustransition of hypertrophy to heart failure. Importantly, changes in gene expression observed during initiation of hypertrophy were significantly different from those seen during its transition to heart failure. Our data show that overexpression of myotrophin results in initiation of cardiac hypertrophy that progresses to heart failure, similar to changes in human heart failure. Knowledge of the changes that take place as a result of overexpression of myotrophin at both the cellular and molecular levels will suggest novel strategies for treatment to prevent hypertrophy and its progression to heart failure.

Abstract 51: Thymosin β4 Targets Wisp1 to Protect Cardiomyocytes in AngII- induced Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sudhiranjan Gupta ◽  
Li Li ◽  
Rakesh Guleria ◽  
Kenneth M Baker
Keyword(s):  
Cardiac Hypertrophy ◽  
Fluorescent Microscopy ◽  
Marker Genes ◽  
Protective Mechanism ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Antiapoptotic Proteins ◽  
Neonatal Cardiomyocytes ◽  
Cell Proliferation And Differentiation ◽  
Pre Treatment

Background: Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tβ4 in cardiomyocytes hypertrophy is currently unknown. The purpose of this study is to dissect the cardio-protective mechanism of Tβ4 in Ang II induced cardiac hypertrophy. Methods: Rat neonatal cardiomyocytes with or without Tβ4 pretreatment were stimulated with Ang II and expression of cell sizes, hypertrophy marker genes and Wnt signaling components was evaluated by quantitative real-time PCR, western blotting and fluorescent microscopy. Selected target gene Wisp-1 was either overexpressed or silenced by siRNA transfections in neonatal cardiomyocytes and effect of Tβ4 in Ang II-induced cardiac hypertrophy was evaluated. Results: Pre-treatment of Tβ4 resulted in reduction of cell sizes, hypertrophy marker genes and WNT-associated gene expression and levels induced by Ang II in cardiomyocytes. Tβ4 pretreatment also resulted in an increase in the expression of antiapoptotic proteins and reduction of Bax/BCl 2 ratio in the cardiomyocytes. Wisp-1 overexpression promotes cardiac hypertrophy and was reversed by pretreatment with Tβ4. Knocking down of Wisp1 partly rescue the cells from hypertrophic response after Tβ4 treatment. Conclusion: This is the first report that demonstrates the effect of Tβ4 on cardiomyocytes hypertrophy and its capability to selectively target Wisp-1 in neonatal cardiomyocytes thus preventing cell death, thereby, protecting the myocardium. Wisp-1 promotes the cardiac hypertrophy which was prevented by Tβ4 treatment.

Abstract 1828: Dyxin/Lmcd1 Mediates Cardiac Hypertrophy Both In Vitro And In Vivo

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Derk Frank ◽  
Robert Frauen ◽  
Christiane Hanselmann ◽  
Christian Kuhn ◽  
Rainer Will ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
The Novel ◽  
Rat Cardiomyocytes ◽  
A Genome

In order to identify new molecular mediators of cardiomyocyte hypertrophy, we performed a genome wide mRNA microarray screen of biomechanically stretched neonatal rat cardiomyocytes (NRCM). We found the novel sarcomeric LIM protein Dyxin/Lmcd1 being significantly upregulated (5.6x, p<0.001). Moreover, Dyxin was also significantly induced in several mouse models of myocardial hypertrophy including aortic banding, calcineurin overexpression and angiotensin stimulation, suggesting a potential role as a mediator of cardiac hypertrophy. To further test this hypothesis, we adenovirally overexpressed Dyxin in NRCM which potently induced cellular hypertrophy (150%, p<0.001) and the hypertrophic gene program (ANF, BNP). Consistent with an induction of calcineurin signalling, the calcineurin-responsive gene Rcan1– 4 (MCIP1.4) was found significantly upregulated (3.2x, p<0.001). Conversely, knockdown of Dyxin (−75% on protein level) via miRNA completely blunted the hypertrophic response to hypertrophic stimuli, including stretch and PE (both p<0.001). Furthermore, PE-mediated activation of calcineurin signaling (Upregulation of Rcan1– 4 by 7.3x, p<0.001) was completely blocked by knockdown of Dyxin. To confirm these results in vivo, we next generated transgenic mice with cardiac-restricted overexpression of Dyxin using the α -MHC promoter. Despite normal cardiac function as assessed by echocardiography, adult transgenic mice displayed significant cardiac hypertrophy in morphometrical analyses (3.9 vs. 3.5 mg/g LV/heart weight, n=8–11, p<0.05). This finding was supplemented by a robust induction of the hypertrophic gene program including ANF (3.7-fold, n=6, p=0.01) and α -skeletal actin (2.8-fold, n=6, p<0.05). Likewise, Rcan1– 4 was found upregulated (+112%, n=5, p<0.05), Taken together, we show that the novel sarcomeric z-disc protein Dyxin/Lmcd1 is significantly upregulated in several models of cardiac hypertrophy and potently induces cardiomyocyte hypertrophy both in vitro and in vivo. Mechanistically, Lmcd1/Dyxin appears to signal through the calcineurin pathway.

scholarly journals Pioglitazone Protected against Cardiac Hypertrophy via Inhibiting AKT/GSK3βand MAPK Signaling Pathways

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Wen-Ying Wei ◽  
Zhen-Guo Ma ◽  
Si-Chi Xu ◽  
Ning Zhang ◽  
Qi-Zhu Tang
Keyword(s):  
Protein Kinase ◽  
Cardiac Hypertrophy ◽  
Glycogen Synthase ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Neonatal Rat ◽  
Aortic Banding ◽  
Hypertrophic Response

Peroxisome proliferator activated receptorγ(PPARγ) has been closely involved in the process of cardiovascular diseases. This study was to investigate whether pioglitazone (PIO), a PPARγagonist, could protect against pressure overload-induced cardiac hypertrophy. Mice were orally given PIO (2.5 mg/kg) from 1 week after aortic banding and continuing for 7 weeks. The morphological examination and biochemical analysis were used to evaluate the effects of PIO. Neonatal rat ventricular cardiomyocytes were also used to verify the protection of PIO against hypertrophy in vitro. The results in our study demonstrated that PIO remarkably inhibited hypertrophic response induced by aortic banding in vivo. Besides, PIO also suppressed cardiac fibrosis in vivo. PIO treatment also inhibited the activation of protein kinase B (AKT)/glycogen synthase kinase-3β(GSK3β) and mitogen-activated protein kinase (MAPK) in the heart. In addition, PIO alleviated angiotensin II-induced hypertrophic response in vitro. In conclusion, PIO could inhibit cardiac hypertrophy via attenuation of AKT/GSK3βand MAPK pathways.

scholarly journals Cped1 promotes chicken SSCs formation with the aid of histone acetylation and transcription factor Sox2

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Chen Zhang ◽  
Fei Wang ◽  
Qisheng Zuo ◽  
Changhua Sun ◽  
Jing Jin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Histone Acetylation ◽  
Histone Deacetylase Inhibitors ◽  
Embryonic Stem ◽  
Control Area ◽  
Luciferase Reporter ◽  
Marker Genes

Spermatogonial stem cells (SSCs) may apply to gene therapy, regenerative medicine in place of embryonic stem cells (ESCs). However, the application of SSCs was severely limited by the low induction efficiency and the lack of thorough analysis of the regulatory mechanisms of SSCs formation. Current evidences have demonstrated multiple marker genes of germ cells, while genes that specifically regulate the formation of SSCs have not been explored. In our study, cadherin-like and PC-esterase domain containing 1 (Cped1) expressed specifically in SSCs based on RNA-seq data analysis. To study the function of Cped1 in the formation of SSCs, we successfully established a CRISPR/Cas9 knockout system. The gene disruption frequency is 37% in DF1 and 25% in ESCs without off-target effects. Knockout of Cped1 could significantly inhibit the formation of SSCs in vivo and in vitro. The fragment of −1050 to −1 bp had the activity as Cped1 gene promoter. Histone acetylation could regulate the expression of Cped1. We added 5-azaeytidi (DNA methylation inhibitors) and TSA (histone deacetylase inhibitors) respectively during the cultivation of SSCs. TSA was validated to promote the transcription of Cped1. Dual-luciferase reporter assay revealed that active control area of the chicken Cped1 gene is −296 to −1 bp. There are Cebpb, Sp1, and Sox2 transcription factor binding sites in this region. Point-mutation experiment results showed that Sox2 negatively regulates the transcription of Cped1. Above results demonstrated that Cped1 is a key gene that regulates the formation of SSCs. Histone acetylation and transcription factor Sox2 participate in the regulation of Cped1.

scholarly journals MuRF1 mono-ubiquitinates TRα to inhibit T3-induced cardiac hypertrophy in vivo

2016 ◽  
Vol 56 (3) ◽  
pp. 273-290 ◽  
Author(s):  
Kristine M Wadosky ◽  
Jessica M Berthiaume ◽  
Wei Tang ◽  
Makhosi Zungu ◽  
Michael A Portman ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Glucocorticoid Receptors ◽  
Hormone Receptors ◽  
Cardiac Injury ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
Hypertrophic Response ◽  
Physiological Cardiac Hypertrophy

Thyroid hormone (TH) is recognized for its role in cellular metabolism and growth and participates in homeostasis of the heart. T3 activates pro-survival pathways including Akt and mTOR. Treatment with T3 after myocardial infarction is cardioprotective and promotes elements of physiological hypertrophic response after cardiac injury. Although T3 is known to benefit the heart, very little about its regulation at the molecular level has been described to date. The ubiquitin proteasome system (UPS) regulates nuclear hormone receptors such as estrogen, progesterone, androgen, and glucocorticoid receptors by both degradatory and non-degradatory mechanisms. However, how the UPS regulates T3-mediated activity is not well understood. In this study, we aim to determine the role of the muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) in regulating T3-induced cardiomyocyte growth. An increase in MuRF1 expression inhibits T3-induced physiological cardiac hypertrophy, whereas a decrease in MuRF1 expression enhances T3's activity both in vitro and in cardiomyocytes in vivo. MuRF1 interacts directly with TRα to inhibit its activity by posttranslational ubiquitination in a non-canonical manner. We then demonstrated that a nuclear localization apparatus that regulates/inhibits nuclear receptors by sequestering them within a subcompartment of the nucleus was necessary for MuRF1 to inhibit T3 activity. This work implicates a novel mechanism that enhances the beneficial T3 activity specifically within the heart, thereby offering a potential target to enhance cardiac T3 activity in an organ-specific manner.

scholarly journals Regulation of SREBP1c Gene Expression in Skeletal Muscle: Role of Retinoid X Receptor/Liver X Receptor and Forkhead-O1 Transcription Factor

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2293-2305 ◽  
Author(s):  
Yasutomi Kamei ◽  
Shinji Miura ◽  
Takayoshi Suganami ◽  
Fumiko Akaike ◽  
Sayaka Kanai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Transcription Factor ◽  
Transgenic Mice ◽  
Regulatory Element ◽  
Liver X Receptor ◽  
Retinoid X Receptor ◽  
Dominant Negative

Sterol regulatory element binding protein 1c (SREBP1c) is a master regulator of lipogenic gene expression in liver and adipose tissue, where its expression is regulated by a heterodimer of nuclear receptor-type transcription factors retinoid X receptor-α (RXRα) and liver X receptor-α (LXRα). Despite the potential importance of SREBP1c in skeletal muscle, little is known about the regulation of SREBP1c in that setting. Here we report that gene expression of RXRγ is markedly decreased by fasting and is restored by refeeding in mouse skeletal muscle, in parallel with changes in gene expression of SREBP1c. RXRγ or RXRα, together with LXRα, activate the SREBP1c promoter in vitro. Moreover, transgenic mice overexpressing RXRγ specifically in skeletal muscle showed increased gene expression of SREBP1c with increased triglyceride content in their skeletal muscles. In contrast, transgenic mice overexpressing the dominant-negative form of RXRγ showed decreased SREBP1c gene expression. The expression of Forkhead-O1 transcription factor (FOXO1), which can suppress the function of multiple nuclear receptors, is negatively correlated to that of SREBP1c in skeletal muscle during nutritional change. Moreover, transgenic mice overexpressing FOXO1 specifically in skeletal muscle exhibited decreased gene expression of both RXRγ and SREBP1c. In addition, FOXO1 suppressed RXRα/LXRα-mediated SREBP1c promoter activity in vitro. These findings provide in vivo and in vitro evidence that RXR/LXR up-regulates SREBP1c gene expression and that FOXO1 antagonizes this effect of RXR/LXR in skeletal muscle.

Characterization of a Megakaryocyte-Specific Enhancer of the Key Hemopoietic Transcription Factor GATA1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 834-834
Author(s):  
Boris Guyot ◽  
Kasumi Murai ◽  
Yuko Fujiwara ◽  
Veronica Valverde-Garduno ◽  
Michele Hammett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Transgenic Mice ◽  
Cell Fate ◽  
Red Cells ◽  
Specific Gene ◽  
Cell Fate Decisions

Abstract Specification and differentiation of the megakaryocyte and erythroid lineages from a common bipotential progenitor provides a well-studied model to dissect binary cell fate decisions. To understand how the distinct megakaryocyte- and erythroid-specific gene programs arise, we have examined the transcriptional regulation of the transcription factor GATA1, that is required for normal maturation of these two lineages. Megakaryocyte- and erythroid-specific mouse (m)GATA1 expression requires the mGata1 enhancer mHS-3.5. Within mHS-3.5, we previously showed that the 3′ 179 base pairs (bp) of mHS-3.5 are required for megakaryocyte but not red cell expression. Here, we show that mHS-3.5 binds key hemopoietic transcription factors in vivo (GATA1, SCL/TAL-1) and is required to maintain histone acetylation in the mGata1 locus in primary megakaryocytes. When deletional constructs containing mHS-3.5 were used to direct GATA1-LacZ reporter gene expression in transgenic mice, a 25 bp element within the 3′ 179bp in mHS-3.5, was critical for megakaryocyte expression. In vitro three uncharacterized DNA-binding activities A, B and C bind to the core of the 25 bp element, and these binding sites are conserved through evolution. Of these, only activity B is present in primary megakaryocytes but not red cells. Furthermore, mutation analysis in transgenic mice reveals that activity B is required for megakaryocyte-specific enhancer function. Bioinformatic analysis shows that sequence corresponding to the binding site for activity B is a previously unrecognised motif present in the cis-elements of other megakaryocyte-specific genes. In summary, we have identified a motif and a DNA-binding activity that are likely to be important in directing a megakaryocyte gene expression program distinct from that in red cells.

Mechanisms of Tumor Suppression by the Hematopoietic Transcription Factor PU.1.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2432-2432
Author(s):  
Mark D McKenzie ◽  
Luisa Cimmino ◽  
Yifang Hu ◽  
Ladina Di Rago ◽  
Sandra Mifsud ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transgenic Mice ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Fetal Liver ◽  
Liver Cells ◽  
Myeloid Lineage ◽  
Fetal Liver Cells

Abstract Abstract 2432 Introduction Acute myeloid leukemia (AML) is a genetically and morphologically heterogeneous disease characterized by the accumulation of immature myeloid lineage cells in the bone marrow and blood. It results from genetic alterations that cause increased self-renewal of myeloid progenitors, accompanied by a block in their normal differentiation programs. Studies in mice and humans have shown that loss of expression of PU.1, a master transcription factor that is critical for lymphoid and myeloid lineage development, is a recurrent feature of AML1. Restoring the PU.1 differentiation program in AML is an attractive therapeutic strategy, but remains elusive due to a poor understanding of PU.1 target genes and tumor suppressive mechanisms. In a novel approach to understanding PU.1 function, we have used in vivo RNA interference to inducibly inhibit and restore PU.1 expression in normal hematopoietic cells and leukemias. Results PU.1 knockdown promotes leukemia in mice We identified several short hairpin RNAs that can effectively knockdown PU.1 (Fig 1A). We infected primary fetal liver cells with the most effective LMP-shPU.1 retroviruses and performed in vitro and in vivo assays to assess the effect of PU.1 knockdown (Fig 1B). We found that PU.1 knockdown drives 1) an increased frequency of blast colony-forming cells and self-generation of granulocytic progenitors in vitro (Fig 1C) and 2) a GFP+ myeloid leukemia after several months characterized by accumulation of cKit+Gr1+Mac1+ cells (Fig 1D, E). These findings verify that shRNA-mediated PU.1 knockdown can effectively disable its tumor suppressive functions. Inducible restoration of PU.1 in leukemia in vivo To identify transcriptional targets of PU.1 in vivo, we utilized a recently generated reversible RNAi strategy that allows acute restoration of endogenous PU.1 expression upon Dox treatment in leukemias driven by PU.1 knockdown2. This TRMPV vector strategy allows tet-regulated co-expression of an shRNA and the fluorescent marker dsRed, with stable expression of GFP to mark infected cells. We transduced fetal liver cells derived from Vav-tTA transgenic mice with TRMPV-shPU.1 to drive reversible PU.1 knockdown across the hematopoietic system of reconstituted recipient mice. In contrast to the myeloid leukemia generated earlier using LMP-shPU.1, these mice developed pre-B cell (CD19+CD25+) leukemia with a latency of several months. To acutely restore endogenous PU.1 expression in leukemia, primary tumor cells were transplanted into several recipient mice to generate a cohort for analysis of Dox responses (Figure 2A). We found that dsRed intensity decreased incrementally upon Dox treatment of leukemic transplant recipient mice allowing FACS sorting of leukemia cells from triplicate untreated mice (dsRedhigh, minimal PU.1 expression) or after three days of Dox treatment (dsRedmid, partially restored PU.1 expression). We identified gene expression changes associated with PU.1 restoration using RNA sequencing (RNA-seq). Development of a transgenic mouse allowing inducible PU.1 knockdown in vivo To further investigate PU.1 target genes in vivo, we have recently generated TRE-GFP-shPU.1 transgenic mice allowing inducible knockdown and restoration of PU.1 in adult mice. To test this strain we crossed it to CAGs-rtTA3 mice and treated bitransgenic mice with Dox. Western blot analysis of GFP+ Gr1+Mac1+ sorted myeloid cells showed effective PU.1 knockdown in vivo. We are currently using these mice to identify PU.1 regulated genes in normal myeloblasts in vivo. Conclusions These studies have identified several new candidate PU.1-regulated genes. Further experiments may shed light on whether there is a common novel tumor suppressive mechanism for PU.1 in myeloid and lymphoid leukemias driven by loss of PU.1. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Rapamycin Prevents Thyroid Hormone-Induced Cardiac Hypertrophy

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3477-3484 ◽  
Author(s):  
James A. Kuzman ◽  
Timothy D. O’Connell ◽  
A. Martin Gerdes
Keyword(s):  
Protein Synthesis ◽  
Cardiac Hypertrophy ◽  
Mammalian Target Of Rapamycin ◽  
Kinase Signaling ◽  
Akt Signaling Pathway ◽  
S6 Kinase ◽  
Neonatal Cardiomyocytes ◽  
Neonatal Cardiomyocyte

Thyroid hormones (THs) have many effects on the cardiovascular system including cardiac hypertrophy. Although THs induce cardiac hypertrophy, the mechanism through which they exert this effect is unknown. We previously found that THs activate signaling related to increased protein synthesis [mammalian target of rapamycin (mTOR) and p70 S6 kinase] in the heart. It is unknown whether this activation contributes to TH-induced hypertrophy or whether it is merely incidental. In this study, we used rapamycin to inhibit mTOR function in mice and neonatal cardiomyocyte cultures treated with THs to test whether mTOR/S6 kinase signaling is involved in TH-mediated cardiac hypertrophy. C57 mice were treated with T4 for 3 d, 1 wk, 2 wk, or 1 month with either placebo, T4 (50 μg/100 g body weight·d), rapamycin (200 μg/100 g body weight·d) or T4/rapamycin by sc slow-release pellets. At the end of the treatment period, hemodynamics and physical data were collected and hearts were frozen for Western blot analysis or myocytes were isolated. The effects of T3 and rapamycin were also investigated using neonatal cardiomyocytes. THs activated specific components of the AKT signaling pathway in vivo and in vitro. THs induced cardiac hypertrophy, which was completely inhibited by rapamycin. Our results suggest that TH-induced hypertrophy is mediated by AKT/mTOR/S6 kinase signaling, which is important in the regulation of protein synthesis, a hallmark of cardiac hypertrophy.

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