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See detailCyclooxygenase-2 contributes to the selective induction of cell death by the endocannabinoid 2-arachidonoyl glycerol in hepatic stellate cells.
Siegmund, S. V.; Wojtalla, A.; Schlosser, M. et al

in Biochemical and biophysical research communications (2016), 470(3), 678-84

The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular ... [more ▼]

The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular mechanisms of this selective induction of HSC death are still unresolved. Interestingly, the inducible isoform of cyclooxygenase, COX-2, can metabolize 2-AG to pro-apoptotic prostaglandin glycerol esters (PG-GEs). We analyzed the roles of COX-2 and endocannabinoid-derived PG-GEs in the differential susceptibility of primary activated HSCs and hepatocytes toward 2-AG-induced cell death. HSCs displayed significant COX-2 expression in contrast to hepatocytes. Similar to 2-AG, treatment of HSCs with PGD2-GE dose-dependently induced cell death independently from cannabinoid receptors that was accompanied by PARP- and caspase 3-cleavage. In contrast to 2-AG, PGD2-GE failed to induce significant ROS formation in HSCs, and depletion of membrane cholesterol did not rescue HSCs from PGD2-GE-induced apoptosis. These findings indicate differential engagement of initial intracellular signaling pathways by 2-AG and its COX-2-derived metabolite PGD2-GE, but similar final cell death pathways. Other PG-GEs, such as PGE2-or PGF2alpha-GE did not induce apoptosis in HSCs. Primary rat hepatocytes were mainly resistant against 2-AG- and PGD2-GE-induced apoptosis. HSCs, but not hepatocytes were able to metabolize 2-AG to PGD2-GE. As a proof of principle, HSCs from COX-2(-/-) mice lacked PDG2-GE production after 2-AG treatment. Accordingly, COX-2(-/-) HSCs were resistant against 2-AG-induced apoptosis. In conclusion, the divergent expression of COX-2 in HSCs and hepatocytes contributes to the different susceptibility of these cell types towards 2-AG-induced cell death due to the generation of pro-apoptotic PGD2-GE by COX-2 in HSCs. Modulation of COX-2-driven metabolization of 2-AG may provide a novel physiological concept allowing the specific targeting of HSCs in liver fibrosis. [less ▲]

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See detailDeletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3.
Ryan, Zachary C.; Craig, Theodore A.; Filoteo, Adelaida G. et al

in Biochemical and biophysical research communications (2015), 467(1), 152-6

The physiological importance of the intestinal plasma membrane calcium pump, isoform 1, (Pmca1, Atp2b1), in calcium absorption and homeostasis has not been previously demonstrated in vivo. Since global ... [more ▼]

The physiological importance of the intestinal plasma membrane calcium pump, isoform 1, (Pmca1, Atp2b1), in calcium absorption and homeostasis has not been previously demonstrated in vivo. Since global germ-line deletion of the Pmca1 in mice is associated with embryonic lethality, we selectively deleted the Pmca1 in intestinal absorptive cells. Mice with loxP sites flanking exon 2 of the Pmca1 gene (Pmca1(fl/fl)) were crossed with mice expressing Cre recombinase in the intestine under control of the villin promoter to give mice in which the Pmca1 had been deleted in the intestine (Pmca1(EKO) mice). Pmca1(EKO) mice were born at a reduced frequency and were small at the time of birth when compared to wild-type (Wt) littermates. At two months of age, Pmca1(EKO) mice fed a 0.81% calcium, 0.34% phosphorus, normal vitamin D diet had reduced whole body bone mineral density (P < 0.037), and reduced femoral bone mineral density (P < 0.015). There was a trend towards lower serum calcium and higher serum parathyroid hormone (PTH) and 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) concentrations in Pmca1(EKO) mice compared to Wt mice but the changes were not statistically significant. The urinary phosphorus/creatinine ratio was increased in Pmca1(EKO) mice (P < 0.004). Following the administration of 200 ng of 1alpha,25(OH)2D3 intraperitoneally to Wt mice, active intestinal calcium transport increased approximately 2-fold, whereas Pmca1(EKO) mice administered an equal amount of 1alpha,25(OH)2D3 failed to show an increase in active calcium transport. Deletion of the Pmca1 in the intestine is associated with reduced growth and bone mineralization, and a failure to up-regulate calcium absorption in response to 1alpha,25(OH)2D3. [less ▲]

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See detailRecombinant Nox4 cytosolic domain produced by a cell or cell-free base systems exhibits constitutive diaphorase activity
Nguyen, Minh Vu Chong UL; Zhang, Leilei; Lhomme, Stanislas et al

in Biochemical and Biophysical Research Communications (2012), 419(3), 453-458

The membrane protein NADPH (nicotinamide adenine dinucleotide phosphate) oxidase Nox4 constitutively generates reactive oxygen species differing from other NADPH oxidases activity, particularly in Nox2 ... [more ▼]

The membrane protein NADPH (nicotinamide adenine dinucleotide phosphate) oxidase Nox4 constitutively generates reactive oxygen species differing from other NADPH oxidases activity, particularly in Nox2 which needs a stimulus to be active. Although the precise mechanism of production of reactive oxygen species by Nox2 is well characterized, the electronic transfer throughout Nox4 remains unclear. Our study aims to investigate the initial electronic transfer step (diaphorase activity) of the cytosolic tail of Nox4. For this purpose, we developed two different approaches to produce soluble and active truncated Nox4 proteins. We synthesized soluble recombinant proteins either by in vitro translation or by bacteria induction. While proteins obtained by bacteria induction demonstrate an activity of 4.4 ± 1.7. nmol/min/nmol when measured against iodonitro tetrazolium chloride and 20.5 ± 2.8. nmol/min/nmol with cytochrome c, the soluble proteins produced by cell-free expression system exhibit a diaphorase activity with a turn-over of 26 ± 2.6. nmol/min/nmol when measured against iodonitro tetrazolium chloride and 48 ± 20.2. nmol/min/nmol with cytochrome c. Furthermore, the activity of the soluble proteins is constitutive and does not need any stimulus. We also show that the cytosolic tail of the isoform Nox4B lacking the first NADPH binding site is unable to demonstrate any diaphorase activity pointing out the importance of this domain. © 2012 Elsevier Inc.. [less ▲]

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See detailTime-resolved analysis of transcriptional events during SNAI1-triggered epithelial to mesenchymal transition
Vetter, G.; Le Béchec, Antony UL; Muller, J. et al

in Biochemical and Biophysical Research Communications (2009), 385(4), 485-91

The transcription regulator SNAI1 triggers a transcriptional program leading to epithelial to mesenchymal transition (EMT), providing epithelial cells with mesenchymal features and invasive properties ... [more ▼]

The transcription regulator SNAI1 triggers a transcriptional program leading to epithelial to mesenchymal transition (EMT), providing epithelial cells with mesenchymal features and invasive properties during embryonic development and tumor progression. To identify early transcriptional changes occurring during SNAI1-induced EMT, we performed a time-resolved genome-scale study using human breast carcinoma cells conditionally expressing SNAI1. The approach we developed for microarray data analysis, allowed identifying three distinct EMT stages and the temporal classification of genes. Importantly, we identified unexpected, biphasic expression profiles of EMT-associated genes, supporting their pivotal role during this process. Finally, we established early EMT gene networks by identifying transcription factors and their potential targets which may orchestrate early events of EMT. Collectively, our work provides a framework for the identification and future systematic analysis of novel genes which contribute to SNAI1-triggered EMT. [less ▲]

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See detailEstrogen receptor alpha interacts with 17beta-hydroxysteroid dehydrogenase type 10 in mitochondria.
Jazbutyte, Virginija; Kehl, Franz; Neyses, Ludwig UL et al

in Biochemical and biophysical research communications (2009), 384(4), 450-4

Estrogen receptor alpha (ERalpha) is present in the nucleus, the cytosol and in mitochondria. The rat ERalpha ligand binding domain was employed as bait in a bacterial two-hybrid screening of a human ... [more ▼]

Estrogen receptor alpha (ERalpha) is present in the nucleus, the cytosol and in mitochondria. The rat ERalpha ligand binding domain was employed as bait in a bacterial two-hybrid screening of a human heart cDNA library to detect novel protein-protein interaction partners of ERalpha in the heart. 17beta-Hydroxysteroid dehydrogenase type 10 (17beta-HSD10), which converts potent (17beta-estradiol) to less potent estrogens (estrone), co-localized with 17beta-HSD10 in the mitochondria of rat cardiac myocytes. GST pull-down experiments confirmed the interaction of ERalpha and 17beta-HSD10. These findings suggest that the ERalpha estrogen receptor might be involved in regulating intracellular estrogen levels by modulating 17beta-HSD10 activity. [less ▲]

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See detailDiscovery of novel inhibitors targeting enoyl-acyl carrier protein reductase in Plasmodium falciparum by structure-based virtual screening.
Nicola, George; Smith, Colin A.; Lucumi Moreno, Edinson UL et al

in Biochemical and biophysical research communications (2007), 358(3), 686-91

There is a dire need for novel therapeutics to treat the virulent malarial parasite, Plasmodium falciparum. Recently, the X-ray crystal structure of enoyl-acyl carrier protein reductase (ENR) in complex ... [more ▼]

There is a dire need for novel therapeutics to treat the virulent malarial parasite, Plasmodium falciparum. Recently, the X-ray crystal structure of enoyl-acyl carrier protein reductase (ENR) in complex with triclosan has been determined and provides an opportunity for the rational design of novel inhibitors targeting the active site of ENR. Here, we report the discovery of several compounds by virtual screening and their experimental validation as high potency PfENR inhibitors. [less ▲]

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See detailPioglitazone reverses down-regulation of cardiac PPARgamma expression in Zucker diabetic fatty rats.
Pelzer, Theo; Jazbutyte, Virginija; Arias-Loza, Paula Anahi et al

in Biochemical and biophysical research communications (2005), 329(2), 726-32

Peroxisome proliferator-activated receptor-gamma (PPARgamma) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models ... [more ▼]

Peroxisome proliferator-activated receptor-gamma (PPARgamma) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models. The functional role of PPARgamma in the diabetic heart, however, is not fully understood. Therefore, we analyzed cardiac gene expression, metabolic control, and cardiac glucose uptake in male Zucker diabetic fatty rats (ZDF fa/fa) and lean ZDF rats (+/+) treated with the high affinity PPARgamma agonist pioglitazone or placebo from 12 to 24 weeks of age. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia as well as lower cardiac PPARgamma, glucose transporter-4 and alpha-myosin heavy chain expression levels were detected in diabetic ZDF rats compared to lean animals. Pioglitazone increased body weight and improved metabolic control, cardiac PPARgamma, glut-4, and alpha-MHC expression levels in diabetic ZDF rats. Cardiac [(18)F]fluorodeoxyglucose uptake was not detectable by micro-PET studies in untreated and pioglitazone treated ZDF fa/fa rats but was observed after administration of insulin to pioglitazone treated ZDF fa/fa rats. PPARgamma agonists favorably affect cardiac gene expression in type-2 diabetic rats via activation and up-regulation of cardiac PPARgamma expression whereas improvement of impaired cardiac glucose uptake in advanced type-2 diabetes requires co-administration of insulin. [less ▲]

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See detailExpression and functional analyses of novel mutations of ATP-binding cassette transporter-1 in Japanese patients with high-density lipoprotein deficiency
Nishida, Y.; Hirano, K.; Tsukamoto, K. et al

in Biochemical and Biophysical Research Communications (2002), 290(2), 713-721

ATP-binding cassette transporter-1 (ABCA1) gene is mutated in patients with familial high-density lipoprotein deficiency (FHD). In order to know the molecular basis for FHD, we characterized three ... [more ▼]

ATP-binding cassette transporter-1 (ABCA1) gene is mutated in patients with familial high-density lipoprotein deficiency (FHD). In order to know the molecular basis for FHD, we characterized three different ABCA1 mutations associated with FHD (G1158A/A255T, C5946T/R1851X, and A5226G/N1611D) with respect to their expression in the passaged fibroblasts from the patients and in the cells transfected with themutated cDNAs. Fibroblasts from the all patients showed markedly decreased cholesterol efflux to apolipoprotein (apo)-Al. In the fibroblasts homozygous for G1158A/A255T, the immunoreactive mass of ABCA1 could not be detected, even when stimulated by 9-cisretinoic acid and 22-R- hydroxycholesterol. In the fibroblasts homozygous for C5946T/R1851X, ABCA1 mRNA was comparable. Because the mutant ABCA1 protein (R1851X) was predicted to lack the epitope for the antibody used, we transfected FLAG-tagged truncated mutant (R1851X/ABCA1-FLAG) cDNA into Cos-7 cells, showing that the mutant protein expression was markedly reduced. The expression of N1611D ABCA1 protein was comparable in both fibroblasts and overexpressing cells, although cholesterol efflux from the cells was markedly reduced. These data indicated that, in the three patients investigated, the abnormalities and dysfunction of ABCA1 occurred at the different levels, providing important information about the expression, regulation, and function of ABCA1. [less ▲]

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See detailEstrogen effects in the myocardium: inhibition of NF-kappaB DNA binding by estrogen receptor-alpha and -beta.
Pelzer, T.; Neumann, M.; de Jager, T. et al

in Biochemical and biophysical research communications (2001), 286(5), 1153-7

We have previously shown that estrogen effects in the heart include direct hormone effects on the myocardium. In a recent study we found that one beneficial effect of estradiol on the myocardium is the ... [more ▼]

We have previously shown that estrogen effects in the heart include direct hormone effects on the myocardium. In a recent study we found that one beneficial effect of estradiol on the myocardium is the inhibition of apoptosis in cardiac myocytes. This effect was associated with a reduction of NF-kappaB activity. In the present study we have analyzed the functional mechanism of NF-kappaB inhibition in the myocardium by estrogen receptors-alpha and -beta. Despite the previous finding that 17-beta-estradiol (10 nM) inhibited the staurosporine-induced binding of p65/p50 NF-kappaB complexes to their cognate DNA elements in cultured rat cardiac myocytes, myocyte extracts showed no change in expression or cellular localization of p65, p50, and IkappaB upon staurosporine or estradiol treatment. Addition of either estrogen receptor-alpha or estrogen receptor-beta as recombinant protein was sufficient to inhibit staurosporine-dependent p65/p50 DNA binding in cardiac myocytes. 17-beta-Estradiol inhibits staurosporine-induced p65/p50 DNA binding associated with apoptotic cell death of cardiac myocytes via estrogen receptors-alpha and -beta. This is not associated with changes in p65, p50 and IkappaB expression or subcellular localization. Thus, inhibition of NF-kappaB activity by estrogenic compounds might inhibit NF-kappaB dependent gene expression such as pro-inflammatory cytokines in the myocardium. [less ▲]

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See detail17beta-estradiol prevents programmed cell death in cardiac myocytes.
Pelzer, T.; Neumann, M.; deJager, T. et al

in Biochemical and biophysical research communications (2000), 268(1), 192-200

The cardioprotective effects of estrogens are clearly established. However, the underlying mechanisms are poorly understood. Because programmed cell death (apoptosis) probably contributes to the loss of ... [more ▼]

The cardioprotective effects of estrogens are clearly established. However, the underlying mechanisms are poorly understood. Because programmed cell death (apoptosis) probably contributes to the loss of cardiac myocytes in heart failure and because estrogens prevent apoptosis in breast cancer cells, we investigated whether the loss of cardiac myocytes by programmed cell death could be prevented by physiological doses of 17beta-estradiol. Apoptosis of cultured cardiac myocytes was induced by staurosporine. 17beta-estradiol (10 nM) had an antiapoptotic effect as determined by morphological analysis, vital staining using the Hoechst dye 33342 and terminal transferase dUTP nick-end labeling (TUNEL). As a potential mechanism for the antiapoptotic effect of 17beta-estradiol we found a reduced activity of the ICE-like protease caspase-3 in hormone-treated myocytes. Furthermore, inhibition of apoptosis by estradiol was associated with a reduced activity of NF-kappaB transcription factors, particularly p65/RelA and p50. To our knowledge, these data provide the first indication that 17beta-estradiol in physiological concentrations inhibits apoptosis in cardiac myocytes. The antiapoptotic effect of estrogens might contribute to the known cardioprotective effect of estrogens and provides a starting point for the development of future treatment options. [less ▲]

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See detailCombined SSCP and heteroduplex analysis of the human plasma membrane Ca(2+)-ATPase isoform 1 in patients with essential hypertension.
Benkwitz, C.; Oberdorf-Maass, S.; Neyses, Ludwig UL

in Biochemical and biophysical research communications (1999), 261(2), 515-20

In recent theories concerning the pathogenesis of essential hypertension, altered calcium homeostasis plays an important role. Increased intracellular Ca(2+) levels have repeatedly been reported in ... [more ▼]

In recent theories concerning the pathogenesis of essential hypertension, altered calcium homeostasis plays an important role. Increased intracellular Ca(2+) levels have repeatedly been reported in different cell types of hypertensive subjects. In vascular smooth muscle cells the plasma membrane Ca(2+)-ATPase (PMCA) represents the most important Ca(2+)-ejection system. Modifications of this pump therefore have been assumed to increase contractile tone of small vessels. For this reason, the purpose of this study was to determine if genetic alterations in the hPMCA1 gene might be associated with arterial hypertension. For detection of polymorphisms all 22 PMCA1 exons from 44 patients with essential hypertension (based on rigorous clinical data in addition to a positive family history) and from 40 normotensives without a family history of hypertension were PCR amplified and subsequently subjected to combined single-strand conformation polymorphism (SSCP) and heteroduplex (HTX) analysis. Despite the high sensitivity of almost 100%, differences could not be identified between hypertensives and normotensives within the two groups. These data indicate that at least in this population PMCA1 polymorphisms are presumably not related to common forms of essential hypertension. Furthermore, the high degree of evolutionary conservation of the PMCA1 gene underlines the pivotal role of this ATPase for cell physiology. [less ▲]

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See detailEffects of estrogen on skeletal myoblast growth.
Kahlert, S.; Grohe, C.; Karas, R. H. et al

in Biochemical and biophysical research communications (1997), 232(2), 373-8

To determine the role of estrogen in skeletal muscle growth, we investigated estrogen receptor-mediated effects on proliferation in skeletal myoblasts. In L6, C2C12 and Sol8 myoblasts estrogen receptor ... [more ▼]

To determine the role of estrogen in skeletal muscle growth, we investigated estrogen receptor-mediated effects on proliferation in skeletal myoblasts. In L6, C2C12 and Sol8 myoblasts estrogen receptor was demonstrated by immunoblotting, immunofluorescence microscopy and transfection studies. Estrone induced a significant increase in myoblast growth whereas 17 beta-estradiol had no effect. Furthermore in L6-cells estrone (c-fos: 3.9-fold, egr-1: 4.6-fold) induced immediate-early gene induction significantly stronger than 17 beta-estradiol (c-fos: 1.7-fold, egr-1: 2.3-fold; p < 0.05). Skeletal myoblasts express functional estrogen receptors. Estrogens differ in the activation of skeletal myoblast growth and immediate-early gene induction. [less ▲]

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See detailQuantification of wild-type mitochondrial DNA and its 4.8-kb deletion in rat organs.
Filser, N.; Margue, Christiane UL; Richter, C.

in Biochemical and biophysical research communications (1997), 233(1), 102-7

Oxidative damage to mitochondrial DNA (mtDNA) is considered a major contributor in aging. An age-dependent increase of oxidative damage and of the quantity of partially deleted mtDNA was reported for ... [more ▼]

Oxidative damage to mitochondrial DNA (mtDNA) is considered a major contributor in aging. An age-dependent increase of oxidative damage and of the quantity of partially deleted mtDNA was reported for several rat and human organs. Here, a systematic investigation of ten different tissues and organs of 20-months-old rats was performed. The amount of mtDNA and age-dependent 4.8 kb deletion (delta mtDNA4834) was determined by competitive polymerase chain reaction, along with the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSHPx). The data were related to the corresponding metabolic rates. MtDNA content was highest in heart and lowest in spleen. delta mtDNA4834 was detected in all ten tissues and organs, and its amount was highest in liver and lowest in intestine. In heart, lung, muscle, and bone-marrow the deletion could not be quantified because of a point mutation, an A-->T transition at position 8107. Activities of SOD and GSHPx were highest in liver and lowest in intestinal mucosa. A negative correlation between mtDNA content and delta mtDNA4834, and a positive correlation between metabolic rate, GSHPx, and the deletion was found. These results suggest that the occurrence of delta mtDNA4834 in rat is related to oxidative stress. [less ▲]

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See detailMitogenic signals control translation of the early growth response gene-1 in myogenic cells.
Maass, A.; Grohe, C.; Oberdorf, S. et al

in Biochemical and biophysical research communications (1994), 202(3), 1337-46

Muscle is a major site of expression of the early growth response gene-1 (Egr-1). To investigate its role in muscle proliferation and/or differentiation we studied the effect of a variety of growth ... [more ▼]

Muscle is a major site of expression of the early growth response gene-1 (Egr-1). To investigate its role in muscle proliferation and/or differentiation we studied the effect of a variety of growth factors on cultured mouse muscle Sol8 cells. Three groups of responses could be distinguished: 1. AII, endothelin, phenylephrine, and PMA induced Egr-1 mRNA accumulation, but the message remained untranslated. These factors induced neither differentiation nor proliferation. 2. Insulin induced differentiation. It stimulated Egr-1 mRNA accumulation, but no translation into the Egr-1 protein was seen. 3. bFGF, PDGF BB, and FCS strongly induced DNA- and protein synthesis (i.e. proliferation) and Egr-1 mRNA accumulation. Only under these conditions was the message translated into protein. We conclude: 1. AII, endothelin, phenylephrine, and PMA elicit a nuclear response in Sol8 muscle cells which may lead to reprogramming of genes unrelated to differentiation or proliferation. 2. Differentiation induces a translational block of the Egr-1 mRNA which is only relieved by mitotic stimuli. 3. These results strongly suggest a pivotal role of Egr-1 in muscle proliferation and define translational control as a new mechanism of Egr-1 regulation. [less ▲]

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See detailHyperosmotic stress induces immediate-early gene expression in ventricular adult cardiomyocytes.
Wollnik, B.; Kubisch, C.; Maass, A. et al

in Biochemical and biophysical research communications (1993), 194(2), 642-6

Mammalian cells possessing osmosensors have long been described in brain and kidney. The genetic basis of the response to hyperosmotic stress has been well characterized in prokaryotes. In contrast, the ... [more ▼]

Mammalian cells possessing osmosensors have long been described in brain and kidney. The genetic basis of the response to hyperosmotic stress has been well characterized in prokaryotes. In contrast, the genetic response of eukaryotic cells is poorly understood. Therefore we investigated the effect of hypertonic NaCl and sucrose solutions on the transcriptional activation of the immediate-early genes (IEGs) egr-1 and c-fos in isolated ventricular adult rat cardiomyocytes. We observed that even small increases in osmolarity to 315 +/- 5 mosmol/l and 370 +/- 8 mosmol/l by hypertonic NaCl solution resulted in dose-dependent induction of egr-1 (4-and 5-fold) and c-fos (3-and 4-fold), respectively. Hypertonic sucrose solution had the same effect on egr-1 and c-fos mRNA levels while increased sucrose concentration under isotonic conditions had no effect. Cardiomyocytes exposed to hypertonic media did not significantly shrink as shown by a cell length measurement. We conclude that isolated adult cardiomyocytes possess an osmoreceptor mechanism which is able to sense even slight changes in osmolarity and to translate these into a transcriptional response of the myocardial IEG program. [less ▲]

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See detailInhibition of endothelin-1 induced myocardial protein synthesis by an antisense oligonucleotide against the early growth response gene-1.
Neyses, Ludwig UL; Nouskas, J.; Vetter, H.

in Biochemical and biophysical research communications (1991), 181(1), 22-7

We explored the role of the recently discovered "early growth response gene-1 (Egr-1)" in the induction of myocardial protein synthesis by endothelin-1. Endothelin-1 stimulated protein synthesis (i.e. 3H ... [more ▼]

We explored the role of the recently discovered "early growth response gene-1 (Egr-1)" in the induction of myocardial protein synthesis by endothelin-1. Endothelin-1 stimulated protein synthesis (i.e. 3H-phenylalanine incorporation) in isolated adult rat cardiomyocytes more than 2-fold. Addition of a 15mer Egr-1 antisense oligodeoxyribonucleotide complementary to the first 5 codons of the Egr-1 mRNA completely blocked endothelin-induced protein synthesis. A single base mismatch in the oligonucleotide sequence abolished the inhibitory effect. T3-induced stimulation of protein synthesis was unaffected by the antisense oligonucleotide. These results indicate that the Egr-1 gene product is involved (putatively as a third messenger) in the signal transduction cascade initiated by endothelin-1 which eventually culminates in the induction of cardiac protein synthesis. [less ▲]

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See detailAction of atrial natriuretic peptide and angiotensin II on the myocardium: studies in isolated rat ventricular cardiomyocytes.
Neyses, Ludwig UL; Vetter, H.

in Biochemical and biophysical research communications (1989), 163(3), 1435-43

Isolated calcium-tolerant rat ventricular cardiomyocytes were used to characterize the effects of atrial natriuretic peptide (ANP), Angiotensin II (AII) and their interaction on the myocardial contraction ... [more ▼]

Isolated calcium-tolerant rat ventricular cardiomyocytes were used to characterize the effects of atrial natriuretic peptide (ANP), Angiotensin II (AII) and their interaction on the myocardial contraction-/relaxation pattern free of interference from other types of cardiac cells. Binding of 125I-ANP showed a KD of 12 pM and approximately 600 binding sites per cell. At 37 degrees C (rate 140 bpm) ANP decreased the contraction maximum with an EC50 of about 70 pM, maximal decrease was 35%. ANP (10(-7) M) raised cellular cyclic-GMP from 0.76+/-0.12 to 1.32+/-0.13 pmole/10(6) cells (73%, p less than 0.05). Angiotensin II increased contractility by a maximum of 32% at 10(-7) M; the EC50 was 8 x 10(-10) M. AII markedly delayed relaxation (reduction of maximum relaxation velocity from 0.092 to 0.063 mm/s; p less than 0.05). ANP (10(-7) M) increased the effect of AII (10(-8) M) on contractility by 66% without changing relaxation parameters significantly. This unexpected interaction may be relevant in pathological conditions where both AII and ANP are stimulated, such as heart failure or secondary hypertension. [less ▲]

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See detailThe cholesterol content of the human erythrocyte influences calcium influx through the channel.
Locher, R.; Neyses, Ludwig UL; Stimpel, M. et al

in Biochemical and biophysical research communications (1984), 124(3), 822-8

In order to study the influence of the cholesterol content on the calcium entry channel, the human red blood cell was used as a model system. The cholesterol to lecithin ratio (C/L ratio) of the membrane ... [more ▼]

In order to study the influence of the cholesterol content on the calcium entry channel, the human red blood cell was used as a model system. The cholesterol to lecithin ratio (C/L ratio) of the membrane was modified experimentally by incubating the cells (15h, 25 degrees) with liposomes of defined C/L ratios. Subsequently, net 45Calcium-influx into the cell was measured by inhibiting the Ca-ejecting ATPase with vanadate. Additionally, the use of nitrendipine, a potent calcium channel inhibitor, during incubation allowed the determination of Ca-influx through the calcium channel. A positive correlation between the 45Ca++-influx and the molar C/L ratio of the membrane was found over a wide C/L range. A molar C/L ratio of 1.4 in the membrane increased calcium influx by 150 % compared to controls (molar C/L ratio = 0.8, calcium influx rate = 100 %), while a molar C/L ratio at less than 0.75 decreased calcium influx by 50 %. We conclude, that the cholesterol content of the membrane greatly influences the calcium channel and thus plays a pivotal role for the availability of calcium as a second messenger. These findings may provide a link between high plasma cholesterol and the development of atherosclerosis as well as enhanced platelet aggregability. [less ▲]

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