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(The FASEB Journal. 1999;13:S17-S22.)
© 1999 FASEB

Regulation of growth in the adult cardiomyocytes

K.-D. SCHLÜTER1 and H. M. PIPER

Physiologisches Institut, Justus-Liebig-Universität, D-35392 Giessen, Germany

1Correspondence: Physiologisches Institut, Justus-Liebig-Universität, Aulweg 129, D-35392 Giessen, Germany. E-Mail: Klaus-Dieter.Schlueter{at}physiologie.med.uni-giessen.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 GROWTH RESPONSE TO...
 MECHANICAL STIMULATION OF...
 POSSIBLE INFLUENCE OF...
 REFERENCES
 
Cardiomyocytes of adult myocardium increase their cellular mass in response to growth stimuli. They undergo hypertrophic growth but they do not proliferate in contrast to immature cardiomyocytes. Growth stimuli of the adult cardiomyocytes include classical growth hormones, various neuroendocrine factors, and the increase in mechanical load. The signal transduction of {alpha}1-adrenoceptor stimulation has been investigated in greatest detail and may therefore be taken as a reference for other humoral stimuli. It involves the activation of protein kinase C (PKC) and, downstream of PKC activation, of two separate signaling pathways, one including the mitogen-activated protein kinase and another including PI3-kinase and p70s6k as key steps. Activation of the first pathway leads to re-expression of fetal genes, activation of the second pathway to a general activation of protein synthesis, and cellular growth. In neonatal cardiomyocytes, mechanical stretch causes growth by an activation of an autocrine mechanism including angiotensin II and endothelin. This mechanism does not operate, however, in adult cardiomyocytes. A mechanism of mechanotransduction has not yet been identified on adult cardiomyocytes but integrins may play a part. In microgravity, the scenario of myocardial growth stimulation is altered. On the systemic level, there are changes in hemodynamic and neuroendocrine regulation that exert indirect effects on the myocardium. Microgravity may also exert a direct cellular effect by the absence of a constant gravitational load component.—Schlüter, K.-D., Piper, H. M. Regulation of growth in the adult cardiomyocytes.


Key Words: adrenoceptors • mechanotransduction • microgravity • MAP kinase • PI3-kinase


   INTRODUCTION
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 ABSTRACT
 INTRODUCTION
GROWTH RESPONSE TO...
 MECHANICAL STIMULATION OF...
 POSSIBLE INFLUENCE OF...
 REFERENCES
 
IN ADULT VERTEBRATES, heart muscle cells have lost the ability to divide (1) . They are terminally differentiated. Adaptation of myocardial mass to increased mechanical load proceeds therefore through cellular hypertrophy, in response to exercise or pathological blood pressure elevation. Excessive hypertrophic growth leads to heart failure and is usually accompanied by a deviation from the mature pattern of cardiac gene expression (2) . In particular, parts of the genetic program of fetal life are re-expressed (3) . Heart muscle cells respond with reduction of cellular mass when mechanical load is reduced (4) . In vivo this can be best observed during a phase of regression from a preexisting hypertrophy. It is as yet unknown whether the continuous presence of a gravitational force on Earth also affects directly the trophic state of the heart muscle.

Apart from mechanical stimuli, heart muscle cells in vivo are under continuous neuroendocrine growth control. Myocardial {alpha}- and ß-adrenoceptors play an important role in rapid functional adjustments of the cardiac pump activity (5) . They also play a key role in structural adaptations of the heart. It has been demonstrated in vitro and in vivo that {alpha}1-adrenoceptor stimulation promotes cardiac hypertrophy (6 , 7 ). This growth-promoting effect of {alpha}1-adrenoceptor stimulation represents a direct effect on the cardiomyocyte because it has also been observed on isolated cardiomyocytes (8-10) .

Mechanical and neuroendocrine factors usually act together. Discrimination of one or the other of these influences in causal analysis in vivo cannot normally be achieved. The basic mechanisms of cardiac growth control have therefore been analyzed in experimental models using isolated cardiomyocytes. In these in vitro models selected growth-regulating stimuli can be studied specifically and influences of cell types other than cardiomyocytes can be excluded. Cell cultures may be prepared from fetal, neonatal, or adult animals. The third type of culture is more difficult to establish and is therefore used less frequently. The resulting cell culture models are different in several respects: immature and mature cardiomyocytes differ considerably in terms of cell size and structure, metabolism, gene expression, and receptor composition (11-13) . Cardiomyocytes from the adult myocardium represent the most appropriate model for studies interested in cardiac growth regulation in adults.

This brief review provides an overview of the signal transduction mechanisms of growth regulation in the adult ventricular cardiomyocyte. The growth response to {alpha}1-adrenoceptor stimulation is chosen as reference because it has been investigated in greatest detail. This review also mentions the current concepts of how mechanical stress triggers cardiac growth. Finally, we discuss the question of how microgravity may affect the growth control of the cardiomyocyte.


   GROWTH RESPONSE TO CATECHOLAMINES
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 INTRODUCTION
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Catecholamines can stimulate three types of adrenergic receptors on cardiomyocytes, namely {alpha}1-, ß1-, and ß2-adrenoceptors. On newly isolated quiescent adult cardiomyocytes, ß-adrenoceptor stimulation does not accelerate protein synthesis. This finding was confirmed on cardiomyocytes from various species (10 , 14 ). It is discussed below that ß-adrenoceptor stimulation may nevertheless influence the trophic state of the cardiomyocyte under specific conditions. Three different events characterize the growth response of cardiomyocytes to {alpha}1-adrenoceptor stimulation. First, it activates the protein synthesis. Second, it causes an increase in the number of ribosomes that in total make up the machinery of protein synthesis. Third, it induces changes in the pattern of gene expression. Examples for the last are the re-expression of the ß-isoform of myosin heavy chain (ß-MHC)2, of the B-type isoform of creatine kinase (CK-B), or of the atrionatriuretic factor (ANF).

What are the intracellular signals involved in the growth response of adult cardiomyocytes to {alpha}1-adrenoceptor stimulation? {alpha}1-Adrenoceptors belong to a classical receptor family. These consist of seven-transmembrane-spanning domains and are linked to G-proteins. Under agonist stimulation, {alpha}1-adrenoceptors activate Gq proteins and subsequently the phospholipase Cß/protein kinase C (PLCß/PKC) pathway. These components of signal transduction are also involved in the hypertrophic response to {alpha}1-adrenoceptor stimulation in cardiomyocytes. First, overexpression of constitutively active {alpha}1B-adrenoceptors causes myocardial hypertrophy (15) . Second, direct stimulation of PKC by phorbol esters increases protein and RNA synthesis and induces re-expression of fetal type proteins (10 , 16 ). Third, inhibition of PKC by pharmacologically different PKC inhibitors antagonizes the hypertrophic response to {alpha}1-adrenoceptor stimulation (10 , 17 ). These results indicate a pivotal role for the PLCß/PKC pathway in the signaling of {alpha}1-adrenoceptors to the hypertrophic growth response of cardiomyocytes.

Intracellular signals, which follow PKC activation under {alpha}1-adrenoceptor stimulation, are only partially characterized. Studies investigating potential downstream targets of PKC focused on the mitogen-activated protein kinase (MAPK) pathway. {alpha}1-Adrenoceptor stimulation activates in a PKC-dependent way classical isoforms of MAPK (p42MAPK and p44MAPK, also known as Erk-2 and Erk-1). On neonatal cardiomyocytes, MAPK activation seems to be required for the activation of protein synthesis (18) . In contrast, on adult cardiomyocytes the inhibition of the MAPK pathway does not prevent the activation of protein and RNA synthesis in response to {alpha}1-adrenoceptor stimulation (19) . Induction of fetal type proteins, however, depends on MAPK activation in either cell type. Under pharmacological inhibition of the MAPK kinase (also known as MEK), {alpha}1-adrenoceptor stimulation no longer induces fetal-type proteins (19) . Downstream targets of the MAPK involved in this transcriptional activation have not yet been characterized on adult cardiomyocytes. One may speculate that MAPK-dependent transcription factors such as Elk-1 are also activated in this cell type. It is important to note that there is no linkage between the hypertrophic growth and the re-expression of fetal-type proteins in cardiomyocytes. This not only holds for cardiomyocytes in vitro, but also for the myocardium in vivo. For example, triiodo-L-thyrodine provokes cardiac hypertrophy in vivo without induction of fetal-type proteins (20) .

Apart from activation of MEK and MAPK, activation of PI3-kinase under {alpha}1-adrenoceptor stimulation represents another intracellular signaling pathway (21) . PI3-kinase is a key enzyme for growth regulation in adult cardiomyocytes. Inhibition of this kinase abolishes the hypertrophic response to {alpha}1-adrenoceptor stimulation (21) . Its activation occurs secondarily to the activation of PKC but independently of the MAPK pathway. Activation of PI3-kinase seems to represent a converging point in intracellular signaling for various growth factors in adult cardiomyocytes. Classical growth factors activate PI3-kinase via receptor tyrosine kinases; neuropeptide Y activates PI3-kinase in a pertussis toxin-sensitive but PKC-independent way (22) .

Downstream of PI3-kinase, activation of p70s6k has been identified as another key step in stimulation of protein synthesis under {alpha}1-adrenoceptor stimulation (23) . This kinase phosphorylates the S6 protein of the 40-S subunit of the ribosomes. This may increase their translational activity. Inhibition of the activation of p70s6k attenuates the growth effect of {alpha}1-adrenoceptor agonists or neuropeptide Y in adult cardiomyocytes. Another factor that contributes to the increase in translational activity is the activation of the peptide chain initiation factor elF-4E. The phosphorylation and therefore activation of this factor depends also on the activation of PKC (24) . In summary, activation of PKC, PI3-kinase, and p70s6k represent key steps of the intracellular signaling that control protein synthesis in adult cardiomyocytes.

Ribosomes represent the cellular machinery for protein synthesis. It seems that in resting cardiomyocytes activation of p70s6k can recruit part of the ribosomes to participate in protein synthesis. In mechanically active cardiomyocytes, however, virtually all ribosomes seem functionally active (25) . In the latter case, presumably corresponding to the normal situation in vivo, de novo synthesis of ribosomal RNA is required for a substantial acceleration of protein synthesis. Under {alpha}1-adrenoceptor stimulation or direct stimulation of PKC, RNA polymerase I is found activated and synthesis of rRNA increased (26) . The stimulation in RNA synthesis is also mediated through PI3-kinase and p70s6k. This indicates that, in addition to the S6 protein of ribosomes, p70s6k has other targets. A candidate has been identified on non-cardiac cells, namely the transcription factor CREM (27) . p70s6k thus seems to directly interfere with transcriptional regulation. Figure 1 summarizes the intracellular signaling pathways of {alpha}1-adrenoceptor stimulation identified on adult cardiomyocytes.



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  		Figure 1. Scheme of intracellular steps involved in the hypertrophic response to {alpha}1-adrenoceptor stimulation. Stimulation of {alpha}1-adrenoceptors cause activation of PKC. Subsequently, PI3-kinase and p70s6k are activated. The mitogen-activated protein kinase kinase (MEK) and the translational initiation factor eIF-4E are also activated in a PKC-dependent manner. p70s6k activates the translational activity of ribosomes and presumably RNA-Polymerase-I, which increases the expression of ribosomal RNA. Translational activity and translational capacity are thus augmented. MEK activation activates the mitogen-activated protein kinase (MAPK) cascade, which may activate transcriptional factors, like Elk-1. This results in an altered phenotype that is characterized by an increased transcription of fetal-type proteins.

Under certain experimental conditions, ß2-adrenoceptor stimulation stimulates cardiac protein and RNA synthesis (28 , 29 ). Such a response is observed in isolated cardiomyocytes after exposure to active transforming growth factor ß1 (TGF-ß1) (30) . It has been hypothesized that this observation has relevance for hearts at the turning point between hypertrophy and heart failure because under these conditions the intramyocardial expression of TGF-ß is up-regulated (31) . On the cellular level, ß2-adrenoceptor stimulation evokes an increase in protein synthesis by a mechanism depending on activation of adenylate cyclase and, subsequently, PI3-kinase and p70s6k (28-30) . Activation of PKC and MAPK is not involved. Even though the upstream signaling steps differ for {alpha}1- and ß2-adrenoceptor stimulation, downstream signaling toward protein synthesis seems the same.

The mechanism causing an increase in cellular RNA mass under ß2-adrenoceptor stimulation differs entirely, however, from that under {alpha}1-adrenoceptor stimulation. Under ß2-adrenoceptor stimulation, RNA mass increases in the absence of accelerated RNA synthesis (28) . The degradation of ribosomal RNA is probably prolonged under these conditions. The induction of ornithine decarboxylase (ODC) seems to play a key role. ODC is the rate-limiting enzyme of the polyamine metabolism. Polyamines are polycationic molecules that stabilize nucleic acids and thereby prolong the half-life of rRNA. ODC itself has an extremely short half-life. Its induction requires transcriptional activation. A causal involvement of ODC in the hypertrophic growth achieved by ß-adrenoceptor stimulation is found in vivo and in isolated cardiomyocytes (32 , 33 ). In spite of the differences in mechanisms, both {alpha}1- or ß2-adrenoceptor stimulation supports the growth response of adult cardiomyocytes by an enlargement of the ribosomal capacity of protein synthesis. This supports the direct activating effect on preexisting ribosomes in favor of an increase in protein synthesis.


   MECHANICAL STIMULATION OF CARDIAC PROTEIN SYNTHESIS
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 INTRODUCTION
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 MECHANICAL STIMULATION OF...
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In vivo, hemodynamic conditions that increase wall tension of the myocardium lead to myocardial hypertrophy. Part of this effect may be mediated indirectly, e.g., through a concomitant augmentation of catecholamine release. In the absence of catecholamines, however, mechanical load is an independent growth stimulus for cardiomyocytes in vitro (24 , 34 ). Cardiomyocytes possess an intrinsic mechanism of mechanosensing. To date, the key element for transmission of a mechanical force into a biochemical cellular response has not been identified. To simulate variable wall tension in the heart, cardiomyocytes were stretched on silica gels. Neonatal cardiomyocytes release angiotensin II in response to stretch, which in turn triggers the autocrine release of endothelin (35) . Endothelin then stimulates cellular protein synthesis. This mode of action has also been discussed for mechanosensing in the adult cardiomyocyte because adult myocardium contains an endogenous renin-angiotensin system and angiotensin-converting enzyme inhibitors can reduce myocardial hypertrophy in vivo (36) . Studies performed on adult cardiomyocytes, however, do not provide evidence for such a mechanism of mechanosensing. Elements of the autocrine signaling identified in neonatal cardiomyocytes, however, were investigated. First, on adult cardiomyocytes angiotensin II stimulates protein synthesis only poorly when compared to other hypertrophic stimuli (37) . Second, endothelin receptor blockade does not antagonize this small effect of angiotensin II, indicating that in adult cardiomyocytes endothelin is not part of the cascade to the small growth response under angiotensin II (37) . Third, mechanical stretch, i.e. passive loading of cells, is only a weak stimulator of growth in adult cardiomyocytes (34) . For the adult cell type, contractile activation provides a much stronger stimulus of protein synthesis than passive load (37) . These latter observations suggest that the mechanosensor is localized at focal contacts and costameres where force is transmitted between the cytoskeleton of a contracting cell and the extracellular matrix. Structural alterations of costameres have been documented during force transmission in adult cardiomyocytes (38) . They couple to integrins, which participate in the hypertrophic response of cardiomyocytes (39) . Figure 2 illustrates the elements of this hypothetical model of mechanotransduction.



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  		Figure 2. Hypothetical mechanism of mechanotransduction in adult cardiomyocytes. The contractile force generated by the contractile apparatus is transmitted to membrane-integrated integrins via costamers. This activates the biochemical coupling of integrins. The intracellular signals thus generated modulate the cellular growth response.

In summary, the mechanism of mechanical growth stimulation in the adult cardiomyocyte is still not known. Neonatal cardiomyocytes seem not to provide an adequate model.


   POSSIBLE INFLUENCE OF MICROGRAVITY ON CARDIOMYOCYTE GROWTH CONTROL
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 ABSTRACT
 INTRODUCTION
 GROWTH RESPONSE TO...
 MECHANICAL STIMULATION OF...
 POSSIBLE INFLUENCE OF...
REFERENCES
 
An increase in mechanical load of cardiomyocytes stimulates myocardial growth. This gives rise to the expectation that reduced mechanical load, for example under hypogravity, causes a reduction in myocardial mass. Indeed, a loss in muscle mass occurs in prolonged journeys in space (40) . In vitro experiments suggest that cardiomyocytes can sense differences in gravitational forces on the cellular level. On neonatal cardiac cells, experimental hypergravity induces the expression of a marker of hypertrophied myocardium, that is the B-isoform of creatine kinase (41) , and it stimulates protein and RNA synthesis. A preliminary study indicates that microgravity reduces the activity of creatine kinase in cardiomyocytes (42) . These results may suggest that hypergravity causes cellular hypertrophy and changes in gene expression as found on Earth in hypertrophied myocardium in vivo and microgravity produces the opposite. Data are too few and too preliminary in quality, however, for a conclusion.

In the intact body, systemic effects of microgravity can also indirectly influence growth control of the cardiomyocytes. Systemic shifts of blood volume alter cardiac preload, namely the diastolic distension of the myocardium. The altered passive stretch of the cardiomyocytes may influence their trophic state. The systemic neuroendocrine regulation also grossly alters in microgravity. This may have numerous effects on the heart, independent of mechanical load (Fig. 3 ). Alterations in plasma catecholamine levels during spaceflights have been documented. Investigations on astronauts of SpaceHab flights indicate an activation of the sympathetic nerve system caused by flight stress. As outlined above, catecholamines exert a direct growth-promoting effect on the myocardium. One may speculate that sympathetic activation partially counteracts the induction of myocardial atrophy under hypogravity. In vivo, the indirect effects of microgravity on cardiomyocyte growth control cannot be distinguished from direct effects. Experimental investigations using isolated cardiomyocytes in micro-, normo-, and hypergravity are needed to make that distinction. Adult cardiomyocytes are preferable because they represent more clearly the heart cell of the adults.



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  		Figure 3. Scheme of direct and indirect growth effects of microgravity. On the systemic level microgravity alters cardiac preload via shifts in the distribution of blood volumes and it changes the neuroendocrine influences on the heart. On the cellular level, absence of a gravitational load component may also exert a direct mechanical effect on cardiomyocyte growth control.


   ACKNOWLEDGMENTS
 
This work has been supported by the Deutsche Forschungsgemeinschaft (Grant Pi 162/11-2).


   FOOTNOTES
 
2 Abbreviations: PKC, protein kinase C; ß-MHC, ß-isoform of myosin heavy chain; CK-B, B-type isoform of creatine kinase; ANF, atrionatriuretic factor; PLCß, phospholipase Cß; MAPK, mitogen-activated protein kinase.


   REFERENCES
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  1. Schwarzfeld, T. A., Jacobson, S. L. (1981) Isolation and development in cell culture of myocardial cells of the adult rat. J. Mol. Cell. Cardiol. 13,563-575[Medline]
  2. Levy, D., Garrison, R. J., Savage, D. D., Kannel, W. B., Castelli, W. P. (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl. J. Med. 322,1561-1566[Abstract]
  3. Boheler, K. R., Schwartz, K. (1992) Gene expression in cardiac hypertrophy. Trends Cardiovasc. Med. 5,172-176
  4. Hill, L. S., Monaghan, M., Richardson, P. J. (1979) Regression of left ventricular hypertrophy during treatment with antihypertensive agents. Br. J. Clin. Pharmacol. 7(Suppl. 2),255S-260S
  5. Furnival, C. M., Linden, R. J., Snow, H. M. (1971) The inotropic and chronotropic effects of catecholamines on the dog heart. J. Physiol. (Lond.) 214,15-28
  6. Zimmer, H. G., Kolbeck-Ruhmkorff, C., Zierhut, W. (1995) Cardiac hypertrophy induced by alpha- and beta-adrenergic receptor stimulation. Cardiosci 6,47-57
  7. Fuller, S. J., Gaitanaki, C. J., Sugden, P. H. (1990) Effects of catecholamines on protein synthesis in cardiac myocates and perfused hearts isolated from adult rats. Biochem. J. 266,727-736[Medline]
  8. Ikeda, U., Tsuruya, Y., Yaginuma, T. (1991) {alpha}1-Adrenergic stimulation is coupled to cardiac myocyte hypertrophy. Am. J. Physiol. 260,H953-H956[Abstract/Free Full Text]
  9. Decker, R. S., Cook, M. G., Behnke-Barclay, M. M., Decker, M. L., Lesch, M., Samarel, S. M. (1993) Catecholamines modulate protein turnover in cultured, quiescent rabbit cardiac myocytes. Am. J. Physiol. 265,H329-H339[Abstract/Free Full Text]
  10. Schlüter, K.-D., Piper, H. M. (1992) Trophic effects of catecholamines and parathyroid hormone on adult ventricular cardiomyocytes. Am. J. Physiol. 263,H1739-H1746[Abstract/Free Full Text]
  11. Takahashi, T., Schunkert, H., Isoyama, S., Wie, J. Y., Nadall-Ginard, B., Grossman, W., Izumo, S. (1992) Age-related differences in the expression of proto-oncogenes and contractile protein genes in response to pressure overload in the rat myocardium. J. Clin. Invest. 89,939-946
  12. Clark, W. A., Rudnick, S. J., Simpson, D. G., LaPres, J. J., Decker, R. S. (1993) Cultured adult cardiac myocytes maintain protein synthesis capacity of intact adult hearts. Am. J. Physiol. 264,H573-H582[Abstract/Free Full Text]
  13. Gu, X. H., Ou, R. C., Casley, D. J., Daly, M. J., Naylor, W. G. (1992) Effect of age on endothelin-1 binding sites in rat cardiac ventricular membranes. J. Cardiovasc. Pharmacol. 19,764-769[Medline]
  14. Clark, W. A., Rudnick, S. J., LaPres, J. J., Lesch, M., Decker, R. S. (1991) Hypertrophy of isolated adult feline heart cells following ß-adrenergic-induced beating. Am. J. Physiol. 261,C530-C542[Abstract/Free Full Text]
  15. Milano, C. A., Dolber, P. C., Rockman, H. A., Bond, R. A., Venable, M. E., Allen, L. F., Lefkowitz, R. J. (1994) Myocardial expression of a constitutively active alpha1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy. Proc. Natl. Acad. Sci. USA 91,10109-10113[Abstract/Free Full Text]
  16. Haneda, T., McDermott, P. J. (1991) Stimulation of ribosomal RNA synthesis during hypertrophic growth of cultured heart cells by phorbol ester. Mol. Cell. Biochem. 104,169-177[Medline]
  17. Bell, D., Schlüter, K.-D., Thou, X. J., McDermott, B. J., Piper, H. M. (1995) Hypertrophic effects of calcitonin gene-related peptide (CGRP) and amylin on adult mammalian ventricular cardiomyocytes. J. Mol. Cell. Cardiol. 27,2433-2443[Medline]
  18. Glennon, P. E., Kaddoura, S., Sale, E. M., Sale, G. J., Fuller, S. J., Sugden, P. H. (1996) Depletion of mitogen-activated protein kinase using an antisense oligonucleotide approach downregulates the phenylephrine-induced hypertrophic response in rat cardiac myocytes. Circ. Res. 78,954-961[Abstract/Free Full Text]
  19. Schlüter, K.-D., Schäfer, M., Taimor, G., Piper, H. M. (1997) Intracellular signaling of {alpha}-adrenoceptor mediated hypertrophy. Pfluegers Arch 433(Suppl. 33),R50
  20. Hannan, R. D., West, A. K. (1991) Adrenergic agonists, but not triiodo-L-thyroidine induce c-fos and c-myc expression in the rat heart. Basic Res. Cardiol. 86,154-164[Medline]
  21. Schlüter, K.-D., Goldberg, Y., Taimor, G., Schäfer, M., Piper, H. M. (1998) Role of phosphatidylinositol 3-kinase activation in the hypertrophic growth of adult ventricular cardiomyocytes. Cardiovasc. Res. 40,174-181[Medline]
  22. Goldberg, Y., Taimor, G., Piper, H. M., Schlüter, K.-D. (1998) Intracellular signaling leads to the hypertrophic effect of neuropeptide Y. Am. J. Physiol. 275,C1207-C1215[Abstract/Free Full Text]
  23. Simm, A., Schlüter, K.-D., Diez, C., Piper, H. M., Hoppe, J. (1998) Activation of p70s6k by ß-adrenoceptor agonists on adult cardiomyocytes. J. Mol. Cell. Cardiol. 30,2059-2067[Medline]
  24. Wada, H., Ivester, C. T., Carabello, B. A., Cooper, G., IVth, McDermott, P. J. (1996) Translational initiation factor eIF-4E. A link between cardiac load and protein synthesis. J. Biol. Chem. 271,8359-8364[Abstract/Free Full Text]
  25. McDermott, P. J., Rothblum, L. I., Smith, M. D., Morgan, H. E. (1989) Accelerated rates of ribosomal RNA synthesis during growth of contracting heart cells in culture. J. Biol. Chem. 264,18220-18227[Abstract/Free Full Text]
  26. Allo, S. N., McDermott, P. J., Carl, L. L., Morgan, H. E. (1991) Phorbol ester stimulation of protein kinase C activity and ribosomal DNA transcription. Role in hypertrophic growth of cultured cardiomyocytes. J. Biol. Chem. 266,22003-22009[Abstract/Free Full Text]
  27. de Groot, R. P., Ballou, L. M., Sassone-Corsi, P. (1994) Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to the mitogen-induced gene expression. Cell 79,81-91[Medline]
  28. Pinson, A., Schlüter, K.-D., Zhou, X. J., Schwartz, K., Kessler-Icekson, G., Piper, H. M. (1993) Alpha- and beta-adrenergic stimulation in cultured adult ventricular cardiomyocytes. J. Mol. Cell. Cardiol. 25,477-490[Medline]
  29. Zhou, X. J., Schlüter, K.-D., Piper, H. M. (1996) Hypertrophic responsiveness to ß2-adrenoceptor stimulation on adult ventricular cardiomyocytes. Mol. Cell. Biochem. 163/164,211-216
  30. Schlüter, K.-D., Zhou, X. J., Piper, H. M. (1995) Induction of hypertrophic responsiveness to isoprenaline by TGF-ß in adult rat cardiomyocytes. Am. J. Physiol. 269,C1311-C1316[Abstract/Free Full Text]
  31. Villarreal, F. J., Dillmann, W. H. (1992) Cardiac hypertrophy-induced changes in mRNA levels for TGF-ß1, fibronectin, and collagen. Am. J. Physiol. 262,H1831-H1866
  32. Bartolome, J., Huguenard, J., Slotkin, T. A. (1980) Role of ornithine decarboxylase in cardiac growth and hypertrophy. Science 210,793-794[Abstract/Free Full Text]
  33. Toraason, M., Luken, M. E., Krueger, J. A. (1990) Cooperative action of insulin and catecholamines on stimulation of ornithine decarboxylase activity in neonatal rat heart cells. J. Mol. Cell. Cardiol. 22,637-644[Medline]
  34. Decker, M. L., Janes, D. M., Barclay, M. M., Harger, L., Decker, R. S. (1997) Regulation of adult cardiocyte growth: effects of active and passive mechanical loading. Am. J. Physiol. 272,H2902-H2918[Abstract/Free Full Text]
  35. Ito, H., Hirata, Y., Adachi, S., Tanaka, M., Tsujino, M., Kioke, A., Nogami, A., Marumo, F., Hiroe, M. (1993) Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J. Clin. Invest. 92,398-403
  36. Wagner, J., Drab, M., Bohlender, J., Amann, K., Wienen, W., Ganten, D. (1998) Effects of AT1 receptor blockade on blood pressure and the renin-angiotensin system in spontaneously hypertensive rats of the stroke prone strain. Clin. Exp. Hypertens. 20,205-221
  37. Wada, H., Zile, M. R., Ivester, C. T., Cooper, G., IVth, McDermott, P. J. (1996) Comparative effects of contraction and angiotensin II on growth of adult feline cardiocytes in primary culture. Am. J. Physiol. 271,H29-H37[Abstract/Free Full Text]
  38. Dankowski, B. A., Imanaka-Yoshida, K., Sanger, J. M., Sanger, J. W. (1992) Costameres are sites of force transmission to the substratum in adult rat cardiomyocytes. J. Cell Biol. 118,1411-1420[Abstract/Free Full Text]
  39. Ross, R. S., Pham, C., Shai, S. Y., Goldhaber, J. I., Fenczik, C., Glembotski, C. C., Ginsberg, M. H., Loftus, J. C. (1998) Beta1 integrins participate in the hypertrophic response of rat ventricular myocytes. Circ. Res. 82,1160-1172[Abstract/Free Full Text]
  40. Riley, D. A., Ellis, S., Slocum, G. R., Satyanarayana, T., Bain, J. L., Sedlak, F. R. (1987) Hypogravity-induced atrophy of rat soleus and extensor digitorum longus muscles. Muscle Nerve 10,560-568[Medline]
  41. Pinson, A., Tirosh, R. (1997) Studying the different signal transduction pathways during stimulation of cultured ventricular cardiomyocytes by hypergravity. J. Mol. Cell. Cardiol. 29,A61
  42. Akins, R. E., Schroedl, N. A., Gonda, S. R., Hartzell, C. R. (1997) Neonatal rat heart cells cultured in simulated microgravity. In Vitro Cell Dev. Biol. Anim. 33,337-343[Medline]



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[Abstract] [Full Text] [PDF]

Home page
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Myocardial remodeling and arrhythmogenesis in moderate cardiac hypertrophy in rats
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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

Home page
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