C-myc protooncogene modulates cardiac hypertrophic growth in transgenic mice

1992 ◽  
Vol 262 (2) ◽  
pp. H590-H597 ◽  
Author(s):  
R. J. Robbins ◽  
J. L. Swain
Keyword(s):  
Transgenic Mice ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Fold Increase ◽  
Cardiac Mass ◽  
Hypertrophic Growth ◽  
Basal Expression ◽  
Pharmacological Stimulation ◽  
Beta Adrenergic Agonist

Protooncogenes such as c-myc have been implicated in the transduction of growth signals in the cardiac myocyte. We examined whether increases in c-myc expression occur in murine heart in vivo as a generalized response to the pharmacological stimulation of myocyte growth. Both triiodothyronine (T3) and the beta-adrenergic agonist isoproterenol were demonstrated to induce a rapid and transient increase in cardiac c-myc mRNA abundance, which preceded an increase in cardiac mass. We then examined whether myocyte growth could be modulated by selectively altering cardiac c-myc expression. The model system used was a strain of transgenic mice exhibiting a 20-fold increase in cardiac c-myc expression. Although in nontransgenic mice the administration of T3 and isoproterenol resulted in similar increases in cardiac mass, in transgenic mice the degree of myocardial growth induced with T3 was significantly greater than that induced with isoproterenol (P less than 0.001). This study demonstrates that increasing the basal expression of c-myc in cardiac myocytes alters the growth response of the heart in vivo to certain hypertrophic stimuli and implicates the c-myc protooncogene in the transduction of selective hypertrophic growth signals in differentiated cardiac myocytes.

scholarly journals The c-myc proto-oncogene regulates cardiac development in transgenic mice.

1990 ◽  
Vol 10 (7) ◽  
pp. 3709-3716 ◽  
Author(s):  
T Jackson ◽  
M F Allard ◽  
C M Sreenan ◽  
L K Doss ◽  
S P Bishop ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mrna Expression ◽  
Cardiac Myocyte ◽  
Cellular Proliferation ◽  
Cardiac Development ◽  
Constitutive Expression ◽  
Transgenic Animals ◽  
Hypertrophic Growth ◽  
Myocyte Proliferation

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of alpha-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.

The c-myc proto-oncogene regulates cardiac development in transgenic mice

1990 ◽  
Vol 10 (7) ◽  
pp. 3709-3716
Author(s):  
T Jackson ◽  
M F Allard ◽  
C M Sreenan ◽  
L K Doss ◽  
S P Bishop ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mrna Expression ◽  
Cardiac Myocyte ◽  
Cellular Proliferation ◽  
Cardiac Development ◽  
Constitutive Expression ◽  
Transgenic Animals ◽  
Hypertrophic Growth ◽  
Myocyte Proliferation

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of alpha-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.

scholarly journals Transient Receptor Potential Ankyrin 1 Activation within the Cardiac Myocyte Limits Ischemia–reperfusion Injury in Rodents

2016 ◽  
Vol 125 (6) ◽  
pp. 1171-1180 ◽  
Author(s):  
Yao Lu ◽  
Honit Piplani ◽  
Stacy L. McAllister ◽  
Carl M. Hurt ◽  
Eric R. Gross
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
In Vivo Model

Abstract Background Recent evidence suggests that cross talk exists between cellular pathways important for pain signaling and ischemia–reperfusion injury. Here, the authors address whether the transient receptor potential ankyrin 1 (TRPA1) channel, important in pain signaling, is present in cardiac myocytes and regulates cardiac ischemia–reperfusion injury. Methods For biochemical analysis of TRPA1, techniques including quantitative polymerase chain reaction, Western blot, and immunofluorescence were used. To determine how TRPA1 mediates cellular injury, the authors used an in vivo model of rat cardiac ischemia–reperfusion injury and adult rat–isolated cardiac myocytes subjected to hypoxia–reoxygenation. Results The authors’ biochemical analysis indicates that TRPA1 is within the cardiac myocytes. Further, using a rat in vivo model of cardiac injury, the TRPA1 activators ASP 7663 and optovin reduce myocardial injury (45 ± 5%* and 44 ± 8%,* respectively, vs. control, 66 ± 6% infarct size/area at risk; n = 6 per group; mean ± SD; *P < 0.001). TRPA1 inhibition also blocked the infarct size–sparing effects of morphine. In isolated cardiac myocytes, the TRPA1 activators ASP 7663 and optovin reduce cardiac myocyte cell death when given during reoxygenation (20 ± 3%* and 22 ± 4%* vs. 36 ± 3%; percentage of dead cells per field, n = 6 per group; mean ± SD; *P < 0.05). For a rat in vivo model of cardiac injury, the infarct size–sparing effect of TRPA1 activators also occurs during reperfusion. Conclusions The authors’ data suggest that TRPA1 is present within the cardiac myocytes and is important in regulating myocardial reperfusion injury. The presence of TRPA1 within the cardiac myocytes may potentially explain why certain pain relievers that can block TRPA1 activation, such as cyclooxygenase-2 inhibitors or some nonsteroidal antiinflammatory drugs, could be associated with cardiovascular risk.

scholarly journals PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

2016 ◽  
Vol 113 (45) ◽  
pp. E7116-E7125 ◽  
Author(s):  
Walter E. Knight ◽  
Si Chen ◽  
Yishuai Zhang ◽  
Masayoshi Oikawa ◽  
Meiping Wu ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Cardiac Myocyte ◽  
Contractile Function ◽  
Causative Role ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Cardiac Myocyte Hypertrophy

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.

scholarly journals A Transgenic Mouse Model to Study Glucose Transporter 4myc Regulation in Skeletal Muscle

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1935-1940 ◽  
Author(s):  
Jonathan D. Schertzer ◽  
Costin N. Antonescu ◽  
Philip J. Bilan ◽  
Swati Jain ◽  
Xudong Huang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Glucose Transporter ◽  
Fold Increase ◽  
Essential Elements ◽  
Glucose Disposal ◽  
Vesicle Membrane ◽  
Muscle Creatine Kinase ◽  
Hindlimb Muscles

Skeletal muscle is the major site for dietary glucose disposal, taking up glucose via glucose transporter 4 (GLUT4). Although subcellular fractionation studies demonstrate that insulin increases GLUT4 density in sarcolemma and transverse tubules, fractionation cannot discern GLUT4 vesicle-membrane association from insertion and exofacial exposure. Clonal muscle cultures expressing exofacially tagged GLUT4 have allowed quantification of GLUT4 exposure at the cell surface, its exocytosis, endocytosis, and partner proteins. We hypothesized that transgenic expression of GLUT4myc in skeletal muscles would provide a useful model to investigate GLUT4 biology in vivo. A homozygous mouse colony was generated expressing GLUT4myc driven by the muscle creatine kinase (MCK) promoter. GLUT4 protein levels were about 3-fold higher in hindlimb muscles of MCK-GLUT4myc transgenic mice compared with littermates (P < 0.05). Insulin (12 nm, 30 min) induced a 2.1-fold increase in surface GLUT4myc detected by immunofluorescence of the exofacial myc epitope in nonpermeabilized muscle fiber bundles (P < 0.05). Glucose uptake and surface GLUT4myc levels were 3.5- and 3-fold higher, respectively, in giant membrane vesicles blebbed from hindlimb muscles of insulin-stimulated transgenic mice compared with unstimulated counterparts (P < 0.05). Muscle contraction also elevated both parameters, an effect partially additive to insulin’s. GLUT4myc immunoprecipitation with anti-myc antibodies avoids interfering with associated intracellular binding proteins. Tether, containing a UBX domain, for GLUT4 coimmunoprecipitated with GLUT4myc and insulin stimulation significantly decreased such association (P < 0.05). MCK-GLUT4myc transgenic mice are thus useful to quantify exofacial GLUT4 exposure at the sarcolemma and GLUT4 binding partners in skeletal muscle, essential elements in the investigation of muscle GLUT4 regulation in physiological and pathological states in vivo.

scholarly journals A growth factor for cardiac myocytes is produced by cardiac nonmyocytes.

1991 ◽  
Vol 2 (12) ◽  
pp. 1081-1095 ◽  
Author(s):  
C S Long ◽  
C J Henrich ◽  
P C Simpson
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cardiac Myocytes ◽  
Transforming Growth Factor Beta ◽  
Cardiac Myocyte ◽  
Transforming Growth Factor ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Hypertrophic Growth

Cardiac nonmyocytes, primarily fibroblasts, surround cardiac myocytes in vivo. We examined whether nonmyocytes could modulate myocyte growth by production of one or more growth factors. Cardiac myocyte hypertrophic growth was stimulated in cultures with increasing numbers of cardiac nonmyocytes. This effect of nonmyocytes on myocyte size was reproduced by serum-free medium conditioned by the cardiac nonmyocytes. The majority of the nonmyocyte-derived myocyte growth-promoting activity bound to heparin-Sepharose and was eluted with 0.75 M NaCl. Several known polypeptide growth factors found recently in cardiac tissue, namely acidic fibroblast growth factor (aFGF), basic FGF (bFGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF alpha), and transforming growth factor beta 1 (TGF beta 1), also caused hypertrophy of cardiac myocytes in a dose-dependent manner. However, the nonmyocyte-derived growth factor (tentatively named NMDGF) could be distinguished from these other growth factors by different heparin-Sepharose binding profiles (TNF alpha, aFGF, bFGF, and TGF beta 1) by neutralizing growth factor-specific antisera (PDGF, TNF alpha, aFGF, bFGF, and TGF beta 1), by the failure of NMDGF to stimulate phosphatidylinositol hydrolysis (PDGF and TGF beta 1), and, finally, by the apparent molecular weight of NMDGF (45-50 kDa). This nonmyocyte-derived heparin-binding growth factor may represent a novel paracrine growth mechanism in myocardium.

Gene expression changes associated with fibronectin-induced cardiac myocyte hypertrophy

2004 ◽  
Vol 18 (3) ◽  
pp. 273-283 ◽  
Author(s):  
Hua Chen ◽  
Xueyin N. Huang ◽  
Alexandre F. R. Stewart ◽  
Jorge L. Sepulveda
Keyword(s):  
Gene Expression ◽  
Cardiac Myocytes ◽  
Matrix Protein ◽  
Cardiac Myocyte ◽  
Tissue Growth ◽  
In Vivo Studies ◽  
Extracellular Matrix Protein ◽  
Myocyte Hypertrophy ◽  
Cardiac Myocyte Hypertrophy

Fibronectin (FN) is an extracellular matrix protein that binds to integrin receptors and couples cardiac myocytes to the basal lamina. Cardiac FN expression is elevated in models of pressure overload, and FN causes cultured cardiac myocytes to hypertrophy by a mechanism that has not been characterized in detail. In this study, we analyzed the gene expression changes induced by FN in purified rat neonatal ventricular myocytes using the Affymetrix RAE230A microarray, to understand how FN affects gene expression in cardiac myocytes and to separate the effects contributed by cardiac nonmyocytes in vivo. Pathway analysis using z-score statistics and comparison with a mouse model of cardiac hypertrophy revealed several pathways stimulated by FN in cardiac myocytes. In addition to the known cardiac myocyte hypertrophy markers, FN significantly induced metabolic pathways including virtually all of the enzymes of cholesterol biosynthesis, fatty acid biosynthesis, and the mitochondrial electron transport chain. FN also increased the expression of genes coding for ribosomal proteins, translation factors, and the ubiquitin-proteasome pathway. Interestingly, cardiac myocytes plated on FN showed elevated expression of the fibrosis-promoting peptides connective tissue growth factor (CTGF), WNT1 inducible signaling pathway protein 2 (WISP2), and secreted acidic cysteine-rich glycoprotein (SPARC). Our data complement in vivo studies and reveal several novel genes and pathways stimulated by FN, pointing to cardiac myocyte-specific mechanisms that lead to development of the hypertrophic phenotype.

scholarly journals Stimulation of the cardiac myocyte Na+-K+ pump due to reversal of its constitutive oxidative inhibition

2015 ◽  
Vol 309 (4) ◽  
pp. C239-C250 ◽  
Author(s):  
Karin K. M. Chia ◽  
Chia-Chi Liu ◽  
Elisha J. Hamilton ◽  
Alvaro Garcia ◽  
Natasha A. Fry ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Nadph Oxidase ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Pump Current ◽  
Reciprocal Relationship ◽  
Ang Ii ◽  
Α Subunit

Protein kinase C can activate NADPH oxidase and induce glutathionylation of the β1-Na+-K+ pump subunit, inhibiting activity of the catalytic α-subunit. To examine if signaling of nitric oxide-induced soluble guanylyl cyclase (sGC)/cGMP/protein kinase G can cause Na+-K+ pump stimulation by counteracting PKC/NADPH oxidase-dependent inhibition, cardiac myocytes were exposed to ANG II to activate NADPH oxidase and inhibit Na+-K+ pump current ( Ip). Coexposure to 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1) to stimulate sGC prevented the decrease of Ip. Prevention of the decrease was abolished by inhibition of protein phosphatases (PP) 2A but not by inhibition of PP1, and it was reproduced by an activator of PP2A. Consistent with a reciprocal relationship between β1-Na+-K+ pump subunit glutathionylation and pump activity, YC-1 decreased ANG II-induced β1-subunit glutathionylation. The decrease induced by YC-1 was abolished by a PP2A inhibitor. YC-1 decreased phosphorylation of the cytosolic p47 phox NADPH oxidase subunit and its coimmunoprecipitation with the membranous p22 phox subunit, and it decreased O2·−-sensitive dihydroethidium fluorescence of myocytes. Addition of recombinant PP2A to myocyte lysate decreased phosphorylation of p47 phox indicating the subunit could be a substrate for PP2A. The effects of YC-1 to decrease coimmunoprecipitation of p22 phox and p47 phox NADPH oxidase subunits and decrease β1-Na+-K+ pump subunit glutathionylation were reproduced by activation of nitric oxide-dependent receptor signaling. We conclude that sGC activation in cardiac myocytes causes a PP2A-dependent decrease in NADPH oxidase activity and a decrease in β1 pump subunit glutathionylation. This could account for pump stimulation with neurohormonal oxidative stress expected in vivo.

Confocal and Electron Microscopy of cultured cardiac myocytes

1993 ◽  
Vol 51 ◽  
pp. 364-365
Author(s):  
D.G. Simpson ◽  
R.L. Price ◽  
M. Terracio ◽  
L. Terracio ◽  
T.K. Borg
Keyword(s):  
Cardiac Myocytes ◽  
Heart Development ◽  
Cardiac Myocyte ◽  
Striated Muscle ◽  
Intercellular Junctions ◽  
Membrane Receptors ◽  
Cell Junctions ◽  
The Many

Early in heart development cardiac myocytes are spherical in shape, intercellular junctions are distributed at irregular intervals around the periphery of the cell, and myofibrillar organization is essentially random. As myocytes mature, they undergo extensive morphogenesis during which the phenotype changes to a tubular rodlike shape, cell junctions congregate at the distal ends of cells to form intercalated disks, and myofibrils become organized in parallel arrays typical of striated muscle. Although not fully understood, it is known that these changes are a result of interactive processes between intracellular components of the cytoskeleton, integrin membrane receptors, and the extracellular matrix (ECM).In vivo studies on the process of cardiac myocyte maturation and myofibrillogenesis are difficult because of the complex biochemical environment of the intact animal and the many extra- and intracellular interactions which are required for proper development and myofibrillogenesis. Unfortunately, in previously available in vitro modelling systems, isolated myocytes spread out over the culture substratum, assume a stellate nonpolar shape, and myofibril organization remains essentially random.

Abstract 154: CCDC80 Functions as a Protein Kinase GI Substrate and is Secreted by Cardiac Myocytes

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Robert M Blanton ◽  
Craig Cooper ◽  
Anja Hergruetter ◽  
Mark Aronovitz ◽  
Timothy D Calamaras
Keyword(s):  
Protein Kinase ◽  
Western Blot ◽  
Cardiac Myocytes ◽  
Cardiac Myocyte ◽  
Pressure Overload ◽  
Future Studies ◽  
Transaortic Constriction ◽  
Human Left Ventricle

Background: Protein kinase G I alpha (PKGIa) inhibits cardiac hypertrophy, remodeling, and dysfunction. Downstream PKGI substrates remain incompletely understood and represent potential novel therapeutic targets for myocardial disease. We previously identified through a molecular screen that PKGIa binds and phosphorylates the protein coiled-coiled domain containing 80 (Ccdc80; also termed SSG1 and URB) in vascular smooth muscle cells. Previous work also identified that Ccdc80 is secreted from adipocytes. However, the expression and secretion of Ccdc80 from the cardiac myocyte has not been investigated. The current study tested the hypothesis that Ccdc80 is expressed in and secreted from the cardiac myocyte. Results: In cultured rat cardiac myocytes (CM), we detected Ccdc80 by western blot. Western blot for Ccdc80 also detected a band of the predicted Ccdc80 molecular weight present in media from these cells, but not in uncultured media. Ccdc80 could be detected in the human left ventricle (LV), though expression did not differ between hearts of normal controls and patients with hypertrophic cardiomyopathy. In the setting of LV pressure overload induced by transaortic constriction (TAC), we observed an increase in Ccdc80 expression in 1 week TAC LVs, compared with sham LVs (5.0 +/- 0.3 arbitrary densitometric units in sham versus 9.6 +/- 0.9 in TAC; n=4 per group). Conclusion: Taken together, our findings identify that the PKGIa substrate Ccdc80 expresses in cardiac myocytes, becomes secreted from CMs, resides in the human heart, and increases in expression in the mouse LV in response to pressure overload. Given the anti-remodeling role of PKGIa, these findings support future studies to understand the in vivo role of Ccdc80 in the cardiovascular system. Future studies will also explore the significance of Ccdc80 secretion from the CM and its potential regulation by PKG.

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