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Kenneth R Chien - One of the best experts on this subject based on the ideXlab platform.
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alchemy and the new age of Cardiac Muscle Cell biology
PLOS Biology, 2005Co-Authors: Kenneth R ChienAbstract:Several studies have claimed to identify Cardiac stem Cells. But what criteria do such Cells have to fulfil before we can be confident about their true potential?
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loss of a gp130 Cardiac Muscle Cell survival pathway is a critical event in the onset of heart failure during biomechanical stress
Cell, 1999Co-Authors: Hisao Hirota, John Ross, Ju Chen, Ulrich A K Betz, Klaus Rajewsky, Yusu Gu, Werner Muller, Kenneth R ChienAbstract:Abstract Biomechanical stress is a major stimulus for Cardiac hypertrophy and the transition to heart failure. By generating mice that harbor a ventricular restricted knockout of the gp130 cytokine receptor via Cre-loxP-mediated recombination, we demonstrate a critical role for a gp130-dependent myocyte survival pathway in the transition to heart failure. Such conditional mutant mice have normal Cardiac structure and function, but during aortic pressure overload, these mice display rapid onset of dilated cardiomyopathy and massive induction of myocyte apoptosis versus the control mice that exhibit compensatory hypertrophy. Thus, Cardiac myocyte apoptosis is a critical point in the transition between compensatory Cardiac hypertrophy and heart failure. gp130-dependent cytokines may represent a novel therapeutic strategy for preventing in vivo heart failure.
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Cardiac Muscle Cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen activated protein kinase family
Journal of Biological Chemistry, 1998Co-Authors: Yibin Wang, Shuang Huang, Valerie P Sah, John Ross, Joan Heller Brown, Jiahuai Han, Kenneth R ChienAbstract:p38 mitogen-activated protein (MAP) kinase activities were significantly increased in mouse hearts after chronic transverse aortic constriction, coincident with the onset of ventricular hypertrophy. Infection of cardiomyocytes with adenoviral vectors expressing upstream activators for the p38 kinases, activated mutants of MAP kinase kinase 3b(E) (MKK3bE) and MAP kinase kinase 6b(E) (MKK6bE), elicited characteristic hypertrophic responses, including an increase in Cell size, enhanced sarcomeric organization, and elevated atrial natriuretic factor expression. Overexpression of the activated MKK3bE in cardiomyocytes also led to an increase in apoptosis. The hypertrophic response was enhanced by co-infection of an adenoviral vector expressing wild type p38 beta, and was suppressed by the p38 beta dominant negative mutant. In contrast, the MKK3bE-induced Cell death was increased by co-infection of an adenovirus expressing wild type p38 alpha, and was suppressed by the dominant negative p38 alpha mutant. This provides the first evidence in any Cell system for divergent physiological functions for different members of the p38 MAP kinase family. The direct involvement of p38 pathways in Cardiac hypertrophy and apoptosis suggests a significant role for p38 signaling in the pathophysiology of heart failure.
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Cardiac Muscle Cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen activated protein kinase family
Journal of Biological Chemistry, 1998Co-Authors: Yibin Wang, Shuang Huang, John Ross, Joan Heller Brown, Kenneth R ChienAbstract:Abstract p38 mitogen-activated protein (MAP) kinase activities were significantly increased in mouse hearts after chronic transverse aortic constriction, coincident with the onset of ventricular hypertrophy. Infection of cardiomyocytes with adenoviral vectors expressing upstream activators for the p38 kinases, activated mutants of MAP kinase kinase 3b(E) (MKK3bE) and MAP kinase kinase 6b(E) (MKK6bE), elicited characteristic hypertrophic responses, including an increase in Cell size, enhanced sarcomeric organization, and elevated atrial natriuretic factor expression. Overexpression of the activated MKK3bE in cardiomyocytes also led to an increase in apoptosis. The hypertrophic response was enhanced by co-infection of an adenoviral vector expressing wild type p38β, and was suppressed by the p38β dominant negative mutant. In contrast, the MKK3bE-induced Cell death was increased by co-infection of an adenovirus expressing wild type p38α, and was suppressed by the dominant negative p38α mutant. This provides the first evidence in any Cell system for divergent physiological functions for different members of the p38 MAP kinase family. The direct involvement of p38 pathways in Cardiac hypertrophy and apoptosis suggests a significant role for p38 signaling in the pathophysiology of heart failure.
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hras dependent pathways can activate morphological and genetic markers of Cardiac Muscle Cell hypertrophy
Journal of Biological Chemistry, 1993Co-Authors: Andrew Thorburn, Jacqueline Thorburn, Seiyu Chen, Scott Powers, H E Shubeita, James R Feramisco, Kenneth R ChienAbstract:We have investigated the role of the proto-oncogene HRas in Cardiac Cell growth and hypertrophy. By direct needle microinjection of activated Ras protein into primary neonatal rat ventricular Cardiac myocytes, we find that, unlike many other Cell types, Ras does not induce DNA synthesis in these Cells. However, injection of activated Ras does induce expression of both the c-Fos and atrial natriuretic factor (ANF) genes. Expression of both these genes is associated with the hypertrophic response in ventricular myocytes suggesting that Ras is involved in the hypertrophic signalling pathway. Ras injection also causes morphological changes in the Cells so that they increase in profile and show changes in the organization of the contractile apparatus. Further support for a role for Ras in the hypertrophic response was obtained from studies showing that activated Ras stimulates ANF promoter activity in transient transfection assays. We also show that a dominant interfering Ras mutant inhibits the hypertrophic stimulation of the ANF promoter by phenylephrine, indicating a role for Ras in the hypertrophic effect of an alpha-adrenergic agonist.
Michael D. Schneider - One of the best experts on this subject based on the ideXlab platform.
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a Cardiac nonproliferation treaty
Science, 2011Co-Authors: Michael D. SchneiderAbstract:A common basis of human mortality is the heart, arising from morphogenetic defects of the organ at birth as well as from the chronic ravages of hypertension and coronary artery disease later in life ( 1 ). A key pathological mechanism is Muscle Cell death, mitigated by only a scant capacity for Muscle Cell renewal. Rescuing Cardiac Muscle Cell number might underlie therapeutic strategies, such as the use of antagonists of Muscle Cell death, stem Cell grafting (now pursued in clinical trials), and activating self-repair by dormant Cardiac stem Cells in the heart ( 2 ). However, the genetic networks that control Cardiac Muscle Cell number are not completely understood. On page 458 of this issue, Heallen et al. ( 3 ) provide insights into a signaling pathway that represses the Cardiac Cell division cycle in mice, and show that impairing this pathway can unleash Cardiac Cell proliferation.
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Unchain my heart: the scientific foundations of Cardiac repair
Journal of Clinical Investigation, 2005Co-Authors: Stefanie Dimmeler, Andreas M. Zeiher, Michael D. SchneiderAbstract:In humans, the biological limitations to Cardiac regenerative growth create both a clinical imperative — to offset Cell death in acute ischemic injury and chronic heart failure — and a clinical opportunity; that is, for using Cells, genes, and proteins to rescue Cardiac Muscle Cell number or in other ways promote more efficacious Cardiac repair. Recent experimental studies and early-phase clinical trials lend credence to the visionary goal of enhancing Cardiac repair as an achievable therapeutic target.
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cyclins that don t cycle cyclin t cyclin dependent kinase 9 determines Cardiac Muscle Cell size
Cell Cycle, 2003Co-Authors: Motoaki Sano, Michael D. SchneiderAbstract:A subset of cyclin-dependent protein kinases--Cdk7, Cdk8, and Cdk9--participates directly, in complex ways, with the fundamental machinery for gene transcription, as elements of general transcription factors whose substrate is the C-terminal domain (CTD) of RNA polymerase II. Here, we review recent data implicating the CTD kinase Cdk9 as a critical determinant of Cardiac hypertrophy, in vitro and in vivo. Diverse trophic signals that increase Cardiac mass all activated Cdk9 (work load, the small G-protein Gaq, and the calcium-dependent phosphatase calcineurin in mouse myocardium; endothelin-1, a hypertrophic agonist, in cultured cardiomyocytes). Little or no change occurred in levels of the kinase or its activator, cyclin T. Instead, in all four hypertrophic models, Cdk9 activation involves the dissociation of 7SK small nuclear RNA (snRNA), an endogenous inhibitor. In culture, dominant-negative Cdk9 blocked ET-1-induced hypertrophy, whereas an anti-sense "knockdown" of 7SK snRNA provoked spontaneous Cell growth. In trans-genie mice, concordant with these results, activation of Cdk9 activity via Cardiac-specific overexpression of cyclin Tl suffices to provoke hypertrophy. Together, these findings implicate Cdk9 activity as a pivotal regulator of pathophysiological heart growth. Because hypertrophy, in turn, is a cardinal risk factor for developing Cardiac pump failure, these results support the logic of examining Cdk9 as a potential drug target in heart disease.
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activation and function of cyclin t cdk9 positive transcription elongation factor b in Cardiac Muscle Cell hypertrophy
Nature Medicine, 2002Co-Authors: Motoaki Sano, Hidemasa Oh, Lloyd H. Michael, Maha Abdellatif, Luigi Bagella, Antonio Giordano, Francesco J Demayo, Michael D. SchneiderAbstract:Hypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per Cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (Gαq, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T–Cdk9. Cdk9 was limiting for Cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium. Note: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print.
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the emerging role of telomerase in Cardiac Muscle Cell growth and survival
Journal of Molecular and Cellular Cardiology, 2002Co-Authors: Michael D. SchneiderAbstract:Abstract H. Oh and M. D. Schneider. The Emerging Role of Telomerase in Cardiac Muscle Cell Growth and Survival.Journal of Molecular and Cellular Cardiology (2002) 34, 717–724. Most mammalian Cells—excepting germ Cells, tumor Cells, and stem Cells, that is—possess a finite replicative life span, manifested by the eventual cessation of Cell proliferation. Clinically, this is germane not just to the overt derangements of Cell growth in cancer, but also to organs such as the heart, in which the capacity for Cell replacement and repair is insufficient to maintain organ function following Cell death. Among the intrinsic mechanisms that control a conserved program of replicative senescence is the enzyme telomerase, which synthesizes the telomeric repeat for end-capping of each chromosome. The implications of telomerase for Cardiac growth have recently begun to be defined. Other functions of telomerase, in maintaining genome integrity, also hold importance for Cardiac Muscle, as a novel means to suppress apoptosis and, thus, salvage myocardium following ischemic injury.
William C. Claycomb - One of the best experts on this subject based on the ideXlab platform.
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Cardiac physiology at the Cellular level use of cultured hl 1 cardiomyocytes for studies of Cardiac Muscle Cell structure and function
American Journal of Physiology-heart and Circulatory Physiology, 2004Co-Authors: S. M. White, Phillip E Constantin, William C. ClaycombAbstract:HL-1 Cells are currently the only cardiomyocyte Cell line available that continuously divides and spontaneously contracts while maintaining a differentiated Cardiac phenotype. Extensive characteriz...
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the 21 day postnatal rat ventricular Cardiac Muscle Cell in culture as an experimental model to study adult cardiomyocyte gene expression
Molecular and Cellular Biochemistry, 2002Co-Authors: May L Lam, Manuela Bartoli, William C. ClaycombAbstract:The purpose of this study was to develop and characterize a cardiomyocyte culture system for use as an experimental model to study the mechanism(s) by which Cardiac Muscle Cells permanently exit the Cell cycle during early neonatal life. Ventricular cardiomyocytes, isolated by retrograde perfusion of hearts from 21-day-old and adult rats, were compared through 10 days of culture. Expression patterns of genes encoding developmentally programmed proteins were determined to be similar between cardiomyocytes cultured from 21-day-old and adult rats, using the reverse transcription polymerase chain reaction. A lacZ-expressing reporter gene was used to test the efficiency of gene delivery in cultured cardiomyocytes. Transfections using cationic liposomes yielded 24 ± 7, 25 ± 7 and 10 ± 1% cardiomyocytes positive for β-galactosidase activity in cultured 1-day, 21-day and adult cardiomyocytes, respectively. Direct needle microinjection resulted in 48 ± 7, 35 ± 6 and 37 ± 5% cardiomyocytes positive for enzymatic activity in 1-day, 21-day and adult cardiomyocytes, respectively. Cell cycle-specific cDNA arrays were used to analyze the expression pattern of Cell cycle-related genes in 12-O-tetradecanoyl-phorbol-13-acetate (TPA)- and non-TPA-treated cultured 21-day cardiomyocytes. Based on the similarity of cultured 21-day to adult ventricular cardiomyocytes and their high transfection efficiencies, we propose the use of cultured cardiomyocytes from 21-day-old rat ventricles as an experimental model system for the study of adult cardiomyocyte gene expression and Cell cycle machinery.
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hl 1 Cells a Cardiac Muscle Cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: William C. Claycomb, Nicholas A. Lanson, Beverly S Stallworth, Daniel B Egeland, Joseph B Delcarpio, Anthony Bahinski, Nicholas J IzzoAbstract:We have derived a Cardiac Muscle Cell line, designated HL-1, from the AT-1 mouse atrial cardiomyocyte tumor lineage. HL-1 Cells can be serially passaged, yet they maintain the ability to contract and retain differentiated Cardiac morphological, biochemical, and electrophysiological properties. Ultrastructural characteristics typical of embryonic atrial Cardiac Muscle Cells were found consistently in the cultured HL-1 Cells. Reverse transcriptase–PCR-based analyses confirmed a pattern of gene expression similar to that of adult atrial myocytes, including expression of α-Cardiac myosin heavy chain, α-Cardiac actin, and connexin43. They also express the gene for atrial natriuretic factor. Immunohistochemical staining of the HL-1 Cells indicated that the distribution of the Cardiac-specific markers desmin, sarcomeric myosin, and atrial natriuretic factor was similar to that of cultured atrial cardiomyocytes. A delayed rectifier potassium current (IKr) was the most prominent outward current in HL-1 Cells. The activating currents displayed inward rectification and deactivating current tails were voltage-dependent, saturated at ≫+20 mV, and were highly sensitive to dofetilide (IC50 of 46.9 nM). Specific binding of [3H]dofetilide was saturable and fit a one-site binding isotherm with a Kd of 140 +/− 60 nM and a Bmax of 118 fmol per 105 Cells. HL-1 Cells represent a Cardiac myocyte Cell line that can be repeatedly passaged and yet maintain a Cardiac-specific phenotype.
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hl 1 Cells a Cardiac Muscle Cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte simian virus 40 t oncogene potassium channels dofetilide
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: William C. Claycomb, Beverly S Stallworth, Daniel B Egeland, Joseph B Delcarpio, Nicholas J Izzo, N Icholas, A Lanson, J B GurdonAbstract:We have derived a Cardiac Muscle Cell line, designated HL-1, from the AT-1 mouse atrial cardiomyocyte tumor lineage. HL-1 Cells can be serially passaged, yet they maintain the ability to contract and retain differentiated Cardiac morphological, biochemical, and electrophysiological properties. Ultrastructural characteristics typical of embry- onic atrial Cardiac Muscle Cells were found consistently in the cultured HL-1 Cells. Reverse transcriptase-PCR-based anal- yses confirmed a pattern of gene expression similar to that of adult atrial myocytes, including expression of a-Cardiac my- osin heavy chain, a-Cardiac actin, and connexin43. They also express the gene for atrial natriuretic factor. Immunohisto- chemical staining of the HL-1 Cells indicated that the distri- bution of the Cardiac-specific markers desmin, sarcomeric myosin, and atrial natriuretic factor was similar to that of cultured atrial cardiomyocytes. A delayed rectifier potassium current (IKr) was the most prominent outward current in HL-1 Cells. The activating currents displayed inward rectification and deactivating current tails were voltage-dependent, satu- rated at > >120 mV, and were highly sensitive to dofetilide (IC50 of 46.9 nM). Specific binding of ( 3 H)dofetilide was saturable and fit a one-site binding isotherm with a Kd of 140 1y2 60 nM and a Bmax of 118 fmol per 10 5 Cells. HL-1 Cells represent a Cardiac myocyte Cell line that can be repeatedly passaged and yet maintain a Cardiac-specific phenotype.
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Control of Cardiac Muscle Cell division.
Trends in cardiovascular medicine, 1992Co-Authors: William C. ClaycombAbstract:Division and proliferation of the terminally differentiated ventricular heart Muscle Cell in the adult mammal is not activated after injury such as that caused by a myocardial infarction. We do not understand how mitosis is irreversibly blocked in these myocytes during early development. Mammalian Cardiac Muscle, unlike skeletal Muscle, cannot regenerate. Knowledge of the mechanisms that control the Cardiac myocyte Cell cycle would allow us to design reagents or procedures to initiate repair or regeneration of the adult myocardium following injury. Ideally, we would like to be able to revert Cardiac Muscle Cells in intact heart Muscle to the biochemical state they were in during early fetal growth when they were actively dividing and proliferating. This article briefly reviews what is currently known about the mechanism which so tightly suppresses the mitotic activity of these highly differentiated Cells.
A. Thorburn - One of the best experts on this subject based on the ideXlab platform.
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Ras activity is required for phenylephrine-induced activation of mitogen-activated protein kinase in Cardiac Muscle Cells.
Biochemical and biophysical research communications, 1994Co-Authors: A. ThorburnAbstract:Abstract The mitogen-activated protein (MAP) kinases are a family of kinases whose activity is implicated in a number of growth and differentiation responses. Recently, we and others have shown that these kinases are activated by agonists which induce Cardiac Muscle Cell hypertrophy. Inhibition of MAP kinase activation prevents some of the phenotypes associated with phenylephrine-induced Cardiac Cell hypertrophy, indicating that this activation is of functional significance. In this communication, we show that active Ras can induce MAP kinase activation in Cardiac Muscle Cells. In addition, phenylephrine-induced activation of the MAP kinases requires Ras activity since a dominant negative Ras mutant (Ala15 Ras) and a Ras-blocking, Raf mutant (C4B Raf) prevent activation of the MAP kinase Erk2 by phenylephrine. These data indicate that phenylephrine signaling to the MAP kinases is mediated through Ras.
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the tyrosine kinase inhibitor genistein prevents α adrenergic induced Cardiac Muscle Cell hypertrophy by inhibiting activation of the ras map kinase signaling pathway
Biochemical and Biophysical Research Communications, 1994Co-Authors: J Thorburn, A. ThorburnAbstract:The alpha-adrenergic agonist, phenylephrine, has been widely used to induce hypertrophy in cultured ventricular myocytes from neonatal rats. We have investigated the role of tyrosine phosphorylation in this signaling pathway using the tyrosine kinase inhibitor, genistein. We find that genistein treatment prevents phenylephrine-induced activation of three promoters (Fos, atrial natriuretic factor, ANF, and the myosin light chain 2, MLC-2), which are activated in the hypertrophic response. Genistein also inhibits phenylephrine-induced activation of the mitogen activated protein (MAP) kinases Erk1 and Erk2 and inhibits GTP loading of the Ras protein. These data demonstrate that a genistein-sensitive step is critical for the activation of the Ras-MAP kinase pathway by phenylephrine and suggest that this pathway is important in the regulation of the hypertrophic response.
William I. Wood - One of the best experts on this subject based on the ideXlab platform.
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cardiotrophin 1 activates a distinct form of Cardiac Muscle Cell hypertrophy assembly of sarcomeric units in series via gp130 leukemia inhibitory factor receptor dependent pathways
Journal of Biological Chemistry, 1996Co-Authors: Kai C Wollert, Masashi Narazaki, Ann B Vernallis, Diane Pennica, Mikiyoshi Saito, John K. Heath, Tadamitsu Kishimoto, Tetsuya Taga, Christopher C Glembotski, William I. WoodAbstract:Abstract Cardiotrophin-1 (CT-1) was recently isolated by expression cloning based on its ability to induce an increase in Cell size in neonatal rat ventricular cardiomyocytes. Sequence similarity data suggested that CT-1 is a novel member of a family of structurally related cytokines sharing the receptor component gp130. The present study documents that gp130 is required for CT-1 signaling in cardiomyocytes, by demonstrating that a monoclonal anti-gp130 antibody completely inhibits c-fos induction by CT-1. Similarly, a leukemia inhibitory factor receptor subunit β (LIFRβ) antagonist effectively blocks the CT-1 induction of c-fos, indicating a requirement for LIFRβ in the hypertrophic response, as well. Upon stimulation with CT-1, both gp130 and the LIFRβ are tyrosine-phosphorylated, providing further evidence that CT-1 signals through the gp130/LIFRβ heterodimer in cardiomyocytes. CT-1 induces a hypertrophic response in cardiomyocytes that is distinct from the phenotype seen after α-adrenergic stimulation, both with regard to Cell morphology and gene expression pattern. Stimulation with CT-1 results in an increase in Cardiac Cell size that is characterized by an increase in Cell length but no significant change in Cell width. Confocal laser microscopy of CT-1 stimulated Cells reveals the assembly of sarcomeric units in series rather than in parallel, as seen after α-adrenergic stimulation. CT-1 induces a distinct pattern of immediate early genes, and up-regulates the atrial natriuretic factor (ANF) gene, but does not affect skeletal α-actin or myosin light chain-2v expression. As evidenced by nuclear run-on transcription assays, both CT-1 and α-adrenergic stimulation lead to an increase in ANF gene transcription. Transient transfection analyses document that, in contrast to α-adrenergic stimulation, the CT-1 responsive cis-regulatory elements are located outside of the proximal 3 kilobase pairs of the ANF 5′-flanking region. These studies indicate that CT-1 can activate a distinct form of myocardial Cell hypertrophy, characterized by the promotion of sarcomere assembly in series, via gp130/LIFRβ-dependent signaling pathways.
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cardiotrophin 1 activates a distinct form of Cardiac Muscle Cell hypertrophy assembly of sarcomeric units in series via gp130 leukemia inhibitory factor receptor dependent pathways
Journal of Biological Chemistry, 1996Co-Authors: Kai C Wollert, Masashi Narazaki, Ann B Vernallis, Diane Pennica, Mikiyoshi Saito, John K. Heath, Tadamitsu Kishimoto, Tetsuya Taga, Christopher C Glembotski, William I. WoodAbstract:Cardiotrophin-1 (CT-1) was recently isolated by expression cloning based on its ability to induce an increase in Cell size in neonatal rat ventricular cardiomyocytes. Sequence similarity data suggested that CT-1 is a novel member of a family of structurally related cytokines sharing the receptor component gp130. The present study documents that gp130 is required for CT-1 signaling in cardiomyocytes, by demonstrating that a monoclonal anti-gp130 antibody completely inhibits c-fos induction by CT-1. Similarly, a leukemia inhibitory factor receptor subunit beta (LIFRbeta) antagonist effectively blocks the CT-1 induction of c-fos, indicating a requirement for LIFRbeta in the hypertrophic response, as well. Upon stimulation with CT-1, both gpl30 and the LIFRbeta are tyrosine-phosphorylated, providing further evidence that CT-1 signals through the gp130/LIFRbeta heterodimer in cardiomyocytes. CT-1 induces a hypertrophic response in cardiomyocytes that is distinct from the phenotype seen after alpha-adrenergic stimulation, both with regard to Cell morphology and gene expression pattern. Stimulation with CT-1 results in an increase in Cardiac Cell size that is characterized by an increase in Cell length but no significant change in Cell width. Confocal laser microscopy of CT-1 stimulated Cells reveals the assembly of sarcomeric units in series rather than in parallel, as seen after alpha-adrenergic stimulation. CT-1 induces a distinct pattern of immediate early genes, and up-regulates the atrial natriuretic factor (ANF) gene, but does not affect skeletal alpha-actin or myosin light chain-2v expression. As evidenced by nuclear run-on transcription assays, both CT-1 and alpha-adrenergic stimulation lead to an increase in ANF gene transcription. Transient transfection analyses document that, in contrast to alpha-adrenergic stimulation, the CT-1 responsive cis-regulatory elements are located outside of the proximal 3 kilobase pairs of the ANF 5'-flanking region. These studies indicate that CT-1 can activate a distinct form of myocardial Cell hypertrophy, characterized by the promotion of sarcomere assembly in series, via gpl30/LIFRbeta-dependent signaling pathways.