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Query: UNIPROT:P06889 (Mol)
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Transforming growth factor-beta 1 (TGF-beta 1) is known to regulate cardiac cell function and its overexpression in the heart is thought to contribute to the development of cardiac hypertrophy and fibrosis. We wished to develop a high efficiency gene transfer method that could be used both in vitro and in vivo and result in the overexpression of TGF-beta 1. For this purpose, we constructed a replication-deficient human adenovirus 5 vector encoding for human TGF-beta 1 and used for control purposes an adenovirus lacZ vector. The adenovirus 5 construct was capable of infecting neonatal rat cardiac myocytes, fibroblasts and VSMCs. Of the three cell types, cardiac myocytes appear more susceptible to infection by the adenovirus 5 construct as assessed through beta-galactosidase staining. Infection of cardiac fibroblasts, myocytes and VSMCs with the hTGF-beta 1 adenovirus leads to the expression of hTGF-beta 1 mRNA and enhanced levels of bioactive and total TGF-beta 1 protein. Infection with hTGF-beta 1 adenovirus also results in enhanced levels of collagen type III gene expression in VSMCs and fibroblasts whereas in cardiac myocytes it leads to increased levels for sarcomeric and beta-actin. Thus, this adenoviral vector might be used for the exploration of in vivo effects of altered levels of cardiac TGF-beta 1.
J Mol Cell Cardiol 1996 Apr
PMID:Adenovirus-mediated overexpression of human transforming growth factor-beta 1 in rat cardiac fibroblasts, myocytes and smooth muscle cells. 873 1

Transitions in sarcomeric alpha-actin and cardiac myosin heavy chain (MHC) gene expression have been useful as molecular markers for the development of cardiac hypertrophy and failure. In simpler model systems, alpha-actin expression has been useful in delineating some of the molecular pathways responsible for its induction following growth stimulation in vitro. In this study, we report that the effects of adrenergic agonists on alpha-actin expression in neonatal cardiocytes is dependent upon the culture conditions. In cardiocytes plated at 5 x 10(4) cells/cm2, skeletal alpha-actin mRNA levels represent 47%, 37% or 42% of total sarcomeric alpha-actin accumulations following administrations of 4 microM norepinephrine (NE), isoproterenol (Iso), or phenylephrine (PE), respectively. Cultured cardiocytes treated with vehicle (ascorbate) only accumulated 19% skeletal alpha-actin. Under these tissue culture conditions, in contrast to data reported previously, skeletal alpha-actin expression is regulated by both alpha- and beta-adrenergic agonist stimulation. Furthermore, we present data showing that an endogenous anti-beta-MHC transcript is regulated by both pressure-overload- or thyroxine-induced cardiac hypertrophy. Although anti-beta-MHC transcripts do not play a major role in regulating beta-MHC gene expression, the presence of this antisense transcript is associated with a novel set of beta-MHC degradation products. In vitro studies, where oligonucleotides complementary to beta-MHC have been introduced into cardiomyocytes, show that the mRNA levels of beta-MHC are decreased by 14-21% within 72 h after addition of the oligonucleotides. This result together with the presence of beta-MHC degradation products suggest that endogenous anti-beta-MHC transcripts may be involved in a post-transcriptional regulatory mechanism affecting the steady-state levels of beta-MHC expression.
Mol Cell Biochem
PMID:Regulation of expression of contractile proteins with cardiac hypertrophy and failure. 873 45

We have analyzed the interactions between two types of sarcomeric proteins: myosin heavy chain (MyHC) and members of an abundant thick filament-associated protein family (myosin-binding protein; MyBP). Previous work has demonstrated that when MyHC is transiently transfected into mammalian nonmuscle COS cells, the expressed protein forms spindle-shaped structures consisting of bundles of myosin thick filaments. Co-expression of MyHC and MyBP-C or -H modulates the MyHC structures, resulting in dramatically longer cables consisting of myosin and MyBP encircling the nucleus. Immunoelectron microscopy indicates that these cable structures are more uniform in diameter than the spindle structures consisting solely of MyHC, and that the myosin filaments are compacted in the presence of MyBP. Deletion analysis of MyBP-H indicates that cable formation is dependent on the carboxy terminal 24 amino acids. Neither the MyHC spindles nor the MyHC/MyBP cables associate with the endogenous actin cytoskeleton of the COS cell. While there is no apparent co-localization between these structures and the microtubule network, colchicine treatment of the cells promotes the formation of longer assemblages, suggesting that cytoskeletal architecture may physically impede or regulate polymer formation/extension. The data presented here contribute to a greater understanding of the interactions between the MyBP family and MyHC, and provide additional evidence for functional homology between MyBP-C and MyBP-H.
Mol Biol Cell 1996 Jan
PMID:Modulation of myosin filament organization by C-protein family members. 874 44

The effects of basic fibroblast growth factor (bFGF) and of insulin-like growth factor-I (IGF-I) on structural (actin cytoskeleton and myofibrillar apparatus) remodeling and on the expression of atrial natriuretic factor (ANF) in adult rat ventricular cardiomyocytes have been followed during the hypertrophy reaction up to 3 weeks in culture. Cells attach to the substratum spread into polygonal shapes with pseudopodia and resume contractile function after 1 week. A well structured actin cytoskeleton with stress fiber-like structures fills the cell bodies and the extensions. In controls and with IGF-I cells grow to the double volume while bFGF induces a four-fold increase. The myofibrillar apparatus follows the actin stress fiber-like structures in growing out into the cell periphery. Immunoreactive ANF granules develop and are concentrated around the nuclear region. The fetally occurring alpha-smooth muscle actin (alpha-sm-actin) is re-expressed in stress fiber-like structures. IGF-I down-regulates alpha-sm-actin and ANF and promotes myofibrillar growth whereas bFGF has the opposite effect by up-regulating alpha-sm-actin (on average five to six times more than in controls as analysed by immunoblotting) and ANF. In addition, bFGF restricts myofibrillar growth with a sharp boundary in the perinuclear region. The most dense packing of alpha-sm-actin in the cytoskeleton is found just outside the area containing the myofibrils; so alpha-sm-actin seems to restrict myofibrillar assembly and growth. These cells are nevertheless beating like the controls. The relative increase of cytoskeletal structures with the concomitant lack of growth of myofibrils, is mostly due to an increase in alpha-sarcomeric actin (alpha-cardiac and alpha-skeletal muscle actin) and in alpha-sm-actin.
J Mol Cell Cardiol 1996 Jan
PMID:Influence of fibroblast growth factor (bFGF) and insulin-like growth factor (IGF-I) on cytoskeletal and contractile structures and on atrial natriuretic factor (ANF) expression in adult rat ventricular cardiomyocytes in culture. 874 11

To characterize alterations in gene expression which may occur during the development of compensated left ventricular pressure overload hypertrophy (CH) and the transition to decompensated congestive heart failure (DH), differential RNA display was used to compare mRNA transcripts from sham operated, 4-week, and 8-week thoracic aorta banded guinea-pigs. Of several regulated transcripts chosen for analysis, one was identified by nucleotide sequence homology as titin, a sarcomeric cytoskeletal protein. By differential display and comparative PCR, titin transcripts were increased in CH and then declined in DH. Comparative PCR of desmin and tubulin demonstrated increased mRNA levels for these cytoskeletal proteins in CH and DH. Western analysis showed associated increases in titin (DH) and desmin (CH and DH) protein expression but no increase in tubulin protein. Isolated Langendorff cardiac mechanics failed to reveal functional differences in either hypertrophy phenotype when microtubules were depolymerized (colchicine 10(-6)M). In summary, the major cytoskeletal proteins are differentially regulated in LV pressure overload hypertrophy and failure. Neither the level of beta-tubulin or its polymerization state appear to affect LV function in this model of cardiac hypertrophy.
J Mol Cell Cardiol 1996 Jul
PMID:The role of the cytoskeleton in left ventricular pressure overload hypertrophy and failure. 884 31

Familial hypertrophic cardiomyopathy is the first primary cardiomyopathy to have yielded to the techniques of modern molecular genetics. In the past few years, four genes responsible for this disease have been identified, all of which code for sarcomeric structural proteins. In addition, structure-function analysis and genotype-phenotype correlation studies have shed significant light on the molecular basis of this disease. It is hoped that within the next few years the application of molecular genetic tools will not only facilitate the diagnosis of hypertrophic cardiomyopathy but will also provide prognostic and therapeutic stratification for more definitive therapy.
Mol Med Today 1996 Sep
PMID:Familial hypertrophic cardiomyopathy: diagnostic and therapeutic implications of recent genetic studies. 888 58

Cardiac fibroblasts constitute greater than 90% of the non-myocyte cells in the heart. Previously, it was established that cardiac fibroblasts are predisposed to transformation into a phenotype with muscle-specific features and that transforming growth factor-beta 1 (TGF-beta 1) is a specific inducer of this event. In this study the hypothesis that TGF-beta 1-induced phenotypic modulation of cardiac fibroblasts is associated with their altered proliferative capacity is tested. Therefore the effects of TGF-beta 1 on DNA synthesis in cardiac fibroblasts under normal conditions of cell culture and in response to a potent mitogen, basic fibroblasts growth factor (bFGF) were determined. The results showed that TGF-beta 1 at 15 ng/ml (a concentration that induces fibroblast "transformation") had a regulatory effect on proliferative capacity of cardiac fibroblasts which varied as the function of cell density in culture. In subconfluent and confluent cultures, pre-treatment of cardiac fibroblasts with TGF-beta 1 for 24 h resulted in a dramatic shift in the bFGF-induced stimulation of DNA synthesis. TGF-beta 1-induced inhibition of DNA synthesis in cardiac fibroblasts coincided with their phenotypic modulation as evidenced by the expression of sarcomeric actin mRNA and morphological changes. Cross-linking studies with [125I]-labeled TGF-beta 1 showed the presence of conventional types I, II and III TGF-beta 1 receptor complexes on cardiac fibroblasts and their binding to TGF-beta 1 under the experimental conditions. In summary, these data indicate that the proliferative capacity of cardiac fibroblasts is controlled by TGF-beta 1. They further suggest that the TGF-beta 1-induced phenotypic modulation of cardiac fibroblasts may be extended to include their altered proliferative capacity.
J Mol Cell Cardiol 1996 Sep
PMID:Regulation of proliferative response of cardiac fibroblasts by transforming growth factor-beta 1. 889 51

Myosin rod protein (MRP), a 155 kDa protein encoded by a gene internal to the Drosophila muscle myosin heavy chain (Mhc) gene, contains the MHC rod domain, but has 77 unique N-terminal residues that exactly replace the MHC motor and light chain binding domains. Originally described as an abundant testis protein, we now demonstrate the MRP also is a major component of myofilaments in Drosophila. Specifically, the Mrp promoter directs the expression of a LacZ reporter transgene in somatic, cardiac and visceral muscles. MRP-specific antibodies detect the protein in detergent-insoluble fractions of muscle extracts and co-localize the protein with MHC to the sarcomeric A-band in immunostained muscles. Immunoblot analysis shows that in a set of adult direct flight muscles (DFM), the ratio of MRP to MHC is 1:3. Chemical cross-link and co-immunoprecipitation experiments using 0.5 M KCl-extracted thick filament proteins indicate that native MRP is a homodimer. Electron microscopy of DFM49, which has a high MRP content, shows in cross section, disordered myofilament packing and a variable thin to thick filament ratio and, in longitudinal section, severely bent thin filaments that are not well associated with thick filaments. In rigor, thick filaments from DFM49 consist of segments with cross bridges that are interspersed with smooth domains lacking cross bridges. These data indicate that MRP is a novel contractile protein that co-integrates with myosin into the thick filament, thereby changing structure and function of the sarcomere.
J Mol Biol 1997 Jan 10
PMID:Myosin rod protein: a novel thick filament component of Drosophila muscle. 899 23

The decreased expression of the sarcoplasmic reticulum Ca(2+)-ATPase associated with cardiac hypertrophy was investigated in cultured neonatal rat cardiac myocytes. Northern blot analysis indicated a significant 55-60% decrease in Ca(2+)-ATPase mRNA levels and after 12 and 24 h of treatment with the phorbol ester phorbol myristate acetate (PMA). Myocytes treated with the phorbol ester for 80 h showed a significant 34% decrease (relative to vehicle-treated control cells) in the levels of Ca(2+)-ATPase protein, and a significant 38% increase in the levels of alpha-sarcomeric actin, as assessed by Western blot analysis using specific antibodies. Immunocytochemistry of myocytes treated for 72 h with the phorbol ester revealed a hypertrophied cell morphology, and showed a marked decrease in Ca(2+)-ATPase staining intensity. Contractile calcium transients were evaluated through the use of indo-1. It was found that the t1/2 for the decline of calcium transient was significantly prolonged by PMA treatment (0.51 +/- 0.15) when compared to controls (0.38 +/- 0.17, P < 0.001). Treatment of myocytes with endothelin-1 also led to a 35% decrease in sarcoplasmic reticulum Ca(2+)-ATPase mRNA levels. It is concluded that phorbol ester treatment of neonatal rat cardiac myocytes induces similar changes in Ca(2+)-ATPase mRNA levels. It is concluded that phorbol ester treatment of neonatal rat cardiac myocytes induces similar changes in Ca(2+)-ATPase gene expression as observed in vivo in the hypertrophied and failing heart. The observed prolongation in t1/2 for [Ca2+]i decline might be due to the observed depressed levels for sarcoplasmic reticulum Ca(2+)-ATPase in PMA treated cells.
J Mol Cell Cardiol 1996 Dec
PMID:Phorbol myristate acetate-induced hypertrophy of neonatal rat cardiac myocytes is associated with decreased sarcoplasmic reticulum Ca2+ ATPase (SERCA2) gene expression and calcium reuptake. 900 63

A trinucleotide repeat polymorphism in the MEF2A gene is described. MEF2A is expressed early in cardiac muscle development; thus the possibility of linkage between this polymorphism and familial cardiomyopathies was investigated in three families not linked to genes coding for known sarcomeric proteins. MEF2A was excluded as a candidate for dilated cardiomyopathy (DCM)(LOD of -9.03) and hypertrophic cardiomyopathy (HCM)(LODs of -5.43 and -2.44) in these families. Because expansion of triplet repeats has been shown to be responsible for several inherited diseases, 121 unrelated HCM probands and 28 unrelated DCM probands were examined for evidence of expansion of this repeat. No expansion of this trinucleotide repeat was seen in any of the 149 cardiomyopathy probands.
Mol Cell Probes 1997 Feb
PMID:Polymorphic trinucleotide repeat in the MEF2A gene at 15q26 is not expanded in familial cardiomyopathies. 907 15


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