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PubMed1996

Role of the thrombin receptor in development and evidence for a second receptor.

Thrombin, a coagulation protease generated at sites of vascular injury, activates platelets, endothelial cells, leukocytes and mesenchymal cells. A G-protein-coupled receptor that is proteolytically activated by thrombin is a target for drug development aimed at blocking thrombosis, inflammation and proliferation. Here we show that although disruption of the thrombin receptor (tr) gene in mice causes about half of the tr-/- embryos to die at embryonic day 9-10, half survive to become grossly normal adult mice with no bleeding diathesis. Strikingly, tr-/- platelets respond strongly to thrombin, whereas tr-/- fibroblasts lose their ability to respond to thrombin. We conclude that the thrombin receptor plays an unexpected role in embryonic development, suggesting a possible new function for the 'coagulation' proteases themselves. Moreover, a second platelet thrombin receptor exists, and different thrombin receptors have tissue-specific roles. This may allow development of therapeutics that will selectively block thrombin's different cellular actions.

Adenosine Triphosphate↗
PubMed1989

Epidermal growth factor receptor localization in the rat and monkey testes.

Epidermal growth factors receptor (EGFR) was localized immunocytochemically in the testes of mature and immature rats and immature monkeys. One polyclonal antibody, recognizing the intracellular domain (RK2) of the receptor, was used to carry out the EGFR immunodetection. The RK2 antibody revealed the presence of the EGFR predominantly in Sertoli cells of mature and immature rats and of immature monkeys, although limited interstitial localization of the EGFR was also discerned in the mature rat. In cultured Sertoli cells of immature rats, grown in the absence of epidermal growth factor (EGF), the EGFR was randomly distributed at the cell surface, whereas after the addition of EGF the receptor became aggregated into distinct focal regions. In addition, EGFR of cultured Sertoli cells exhibited autophosphorylation activity upon stimulation with EGF, but failed to transcytose iodinated EGF across a permeability barrier formed by the cultured cells. Instead, all of the added iodinated EGF was internalized and degraded.

Animals↗
PubMed1992

Platelet activation by cross-linking HLA class I molecules and Fc receptor.

The effect on platelet activation of monoclonal antibodies directed against common determinants of the HLA class I heavy chain molecule was studied. Cross-linking W6/32, an anti-HLA class I of IgG2a subclass, led to platelet activation. Two other antibodies of the same subclass did not have this effect on platelets. The lack of activity of the F(ab')2 fragments suggests that the activation signal is mediated by the platelet Fc receptor (Fc gamma RII). Indeed, except for a higher sensitivity of W6/32 to aspirin and apyrase, activations by cross-linking IV-3 (an anti-Fc gamma RII) and W6/32 are similar at the level of InsP3 formation, calcium mobilization, pH modifications, and activation of protein kinase C and myosin kinase. When HLA class I molecules and Fc gamma RII are cross-linked together, platelet activation occurs. This is not observed when a control IgG2a is substituted for W6/32 or when CD9 and Fc receptor are cross-linked together. This suggests that HLA class I molecules and Fc gamma RII synergize to activate platelets.

Adenosine Diphosphate↗
PubMed1985

Spasm of the coronary arteries: causes and consequences (the scientist's viewpoint).

Both beta 1- and alpha 1-adrenoceptors are present on canine coronary arteries, and they are accessible to norepinephrine released from the sympathetic nerves. Under normal conditions, these arteries relax because of the predominance of the beta 1-adrenoceptors, whereas constriction prevails in the presence of beta 1-adrenoceptor antagonists. The coronary arteries also have cholinergic nerves. When activated, these nerves release acetylcholine, which acts on muscarinic receptors on the sympathetic nerve terminals to reduce the output of norepinephrine and thereby lessen the relaxation mediated by beta 1-adrenoceptors. Thus, muscarinic agonists can precipitate coronary artery spasm. If the smooth muscle cells of the coronary arteries become hypoxic, their responsiveness to beta-adrenergic stimulation is lost and constrictor responses are exaggerated. Cardiac glycosides prevent the predominance of the beta-adrenergic effects of norepinephrine. Therefore, after treatment with ouabain, release of norepinephrine from the sympathetic nerves leads not to relaxation but to further contraction of coronary arteries. The endothelium of the coronary arteries inhibits platelet aggregation by the formation and release of prostacyclin, and it reacts to platelet products by causing relaxation of the underlying smooth muscle. In addition, if any thrombin is formed, it also causes endothelium-mediated relaxation. If the endothelium is damaged, these protective mechanisms are lost. Patients with coronary artery spasm usually have morphologic changes in the artery at the site of the spasm. Platelets can aggregate at this site and release vasoactive substances, which--aided by formation of thrombin--cause contraction. Thus, the blood supply to the myocardium is reduced; the ensuing hypoxia augments the constriction. Acute myocardial ischemia caused by coronary vasospasm may precipitate acute cardiac rhythm disturbances and sudden death by ventricular tachycardia or fibrillation.

Adrenergic beta-Agonists↗
PubMed2000

Effect of leptin in platelet and endothelial cells. Obesity and arterial thrombosis.

We demonstrated that leptin showed effects on both platelets and endothelial cells through its functional receptor. These effects are the vector to inducing thrombotic tendency. Leptin concentrations used in our experiments correspond to that of leptin in the circulation of obese individuals. Thus we suggest that increased leptin may act as a risk factor for thrombosis in obese individuals.

Adenosine Diphosphate↗
PubMed1990

Cross-linking of T-cell surface molecules CD4 and CD8 stimulates phosphorylation of the lck tyrosine protein kinase at the autophosphorylation site.

p56lck, a lymphocyte-specific tyrosine protein kinase, binds to the cytoplasmic tails of the T-cell surface molecules CD4 and CD8. Cross-linking of CD4 expressed on the surface of murine thymocytes, splenocytes, and CD4+ T-cell lines induced tyrosine phosphorylation of p56lck dramatically. Cross-linking of CD8 stimulated tyrosine phosphorylation of p56lck strongly in murine L3 and GA4 cells, slightly in splenocytes, but not detectably in thymocytes. Differing effects of cross-linking on in vitro tyrosine kinase activity of p56lck were observed. An increase in the in vitro kinase activity of p56lck, when assayed with [Val5]-angiotensin II as an exogenous substrate, was found to accompany cross-linking of CD4 in three cell lines. No stimulation of the in vitro kinase activity, however, was observed after cross-linking of CD8 in L3 cells. The phosphorylation of p56lck at Tyr-394, the autophosphorylation site, was stimulated by cross-linking in all cell lines examined. Tyr-394 was the predominant site of increased tyrosine phosphorylation in two leukemic cell lines. In the other two cell lines, the phosphorylation of both Tyr-394 and an inhibitory site, Tyr-505, was found to increase. In contrast to cross-linking with antibodies, no striking increase in the tyrosine phosphorylation of p56lck was stimulated by antigenic stimulation. Therefore, the effect of antibody-induced aggregation of CD4 and CD8 on the tyrosine phosphorylation of p56lck differs, at least quantitatively, from what occurs during antigen-induced T-cell activation.

Animals↗
PubMed2002

Human platelets express heat shock protein receptors and regulate dendritic cell maturation.

Immunizations using the endoplasmic reticulum-resident heat shock protein Gp96 induce specific immune responses. Specificity is based on the major histocompatibility complex class I-restricted cross-presentation of Gp96-associated peptides derived from endogenous proteins. Initiation of the immune response depends on the ability of Gp96 to induce the production of proinflammatory cytokines by macrophages and dendritic cells (DCs) and of their maturation in a fashion presumably independent of associated peptide. Both events are mediated by Gp96 receptors on antigen-presenting cells. It is known that Gp96 is released from cells at necrosis induced, for example, by virus infection. Although this event supports the efficient induction of immune responses, it might also interfere with processes that are susceptible to chronic inflammation, such as wound healing after tissue damage. Therefore, Gp96-mediated stimulation of the immune system requires tight regulation. Here we show that human thrombocytes specifically interact with Gp96 and that binding of Gp96 to platelets is enhanced more than 10-fold on activation by thrombin. Gp96 interferes with neither thrombin-induced platelet activation nor platelet aggregation. However, the presence of platelets during Gp96-mediated DC activation reduces the secretion of proinflammatory cytokines and the activation of DCs. This effect is independent of soluble platelet factors and cell-to-cell contact between DCs and thrombocytes. Thus, we provide evidence for a regulatory mechanism that neutralizes Gp96 molecules systemically, especially in the blood. This effect might be of significance in wounds in which chronic inflammation and immune responses against autoantigens have to be prevented.

Antigens, Neoplasm↗
PubMed1992

Response of human platelets to activating monoclonal antibodies: importance of Fc gamma RII (CD32) phenotype and level of expression.

Certain monoclonal antibodies (MoAbs) specific for platelet membrane glycoproteins are known to be capable of activating platelets, and it is generally thought that platelets from normal subjects are equally susceptible to stimulation by such MoAbs. We found that platelets from 20 normal donors varied significantly in their sensitivity to three IgG1 murine MoAbs specific for membrane glycoproteins CD9, GPIV (CD36), and the GPIIb/IIIa complex (CD41), respectively. The response of platelets to these MoAbs was blocked by prior addition of MoAb IV.3 specific for the Fc gamma RII receptor, indicating that activation was Fc receptor mediated. Platelets that responded poorly to these MoAbs failed to bind the MoAb 41H.16, specific for the "responder" form of Fc gamma RII, but platelets that responded well reacted with this MoAb. The average number of Fc gamma RII receptors on platelets from "responders" and "non-responders" was approximately the same. However, the number of Fc gamma RII receptors expressed influenced sensitivity of a subgroup of "responder" platelets to the anti-CD41 MoAb. These platelets were judged on the basis of MoAb binding studies to be heterozygous for the two alleles of Fc gamma RIIA. In contrast to their varying sensitivity to IgG1 MoAbs, members of the platelet panel responded equally well to 50H.19, an IgG2a MoAb specific for CD9, and these responses could not be blocked by MoAb IV.3 in the presence of plasma. This appears to be because of dual actions of 50H.19 on platelets: one FcR-dependent and the other complement-dependent. Our findings confirm previous reports that certain IgG1 MoAbs activate platelets through binding of their Fc domains to Fc gamma RII receptors and demonstrate that this response is influenced both by Fc gamma RII phenotype and (in the case of the anti-CD41 MoAb) by the number of Fc gamma RII receptors expressed. The failure of nonresponding platelets to bind detectable amounts of MoAb 41H.16, which is thought to recognize all Fc gamma RII receptors except for one allele of the Fc gamma RIIA gene, is consistent with the possibility that Fc gamma RIIA gene products, but not Fc gamma RIIB or Fc gamma RIIC gene products, are expressed on platelets.

Animals↗
PubMed2005

Effects of benzyl alcohol on aggregation of recombinant human interleukin-1-receptor antagonist in reconstituted lyophilized formulations.

A major limitation in the successful development of multidose protein formulations is protein aggregation induced by antimicrobial preservatives such as benzyl alcohol, which are included to maintain product sterility. Studies were conducted to evaluate the strategy of developing lyophilized formulations of a therapeutic protein, recombinant human interlukin-1 receptor antagonist (rhIL-1ra), to be reconstituted with a bacteriostatic amount (0.9% w/v) of benzyl alcohol in water. The strategy was based on the following hypotheses. The first was that benzyl alcohol would foster aggregation during reconstitution of the lyophilized sample. The second hypothesis was that the extent of benzyl alcohol-induced protein aggregation would correlate directly with the degree of structural perturbation of rhIL-1ra in the dried solid after lyophilization. Differential structural retention of rhIL-1ra in the dried solid was obtained by using a combination of formulation variables important for lyophilization and included: protein concentration, type of stabilizer, and presence or absence of NaCl. Infrared spectroscopic analysis of the lyophilized samples indicated that high initial solution protein concentration and the stabilizer sucrose minimized structural perturbation of rhIL-1ra during lyophilization. In contrast, NaCl was destabilizing. Reconstitution of the dried solid with 0.9% (w/v) benzyl alcohol caused a greater degree of protein aggregation than reconstitution with water, confirming our first hypothesis. In support of our second hypothesis, the extent of aggregation induced by benzyl alcohol during reconstitution was strongly modulated by the degree of retention of native rhIL-1ra secondary structure during lyophilization. During storage of the reconstituted lyophilized samples at room temperature, benzyl alcohol did not accelerate aggregation of rhIL-1ra. This study demonstrated that for development a multidose lyophilized protein formulation involving reconstitution with a solution of benzyl alcohol, protein structural perturbations during freeze-drying should be minimized with a stabilizing excipient and appropriate choice of protein concentration and tonicity modifier. Furthermore, postreconstitution storage at reduced temperature (e.g., room temperature or 4 degrees C) could minimize the risk of preservative-induced protein aggregation.

Benzyl Alcohol↗
PubMed1988

The effect of the thromboxane receptor antagonist BM 13.177 on experimentally induced coronary artery thrombosis in the pig.

We studied the effect of pretreatment with two doses of the thromboxane antagonist BM 13.177 and its solvent on the development of electrically induced coronary artery thrombosis in pigs. Results were compared with those obtained in animals pretreated with intravenously administered acetylsalicylate and its solvent. The effects of both compounds on the overall cardiovascular performance (heart rate, mean arterial blood pressure, cardiac output, systemic vascular resistance) were minimal. In the animals receiving solvent or acetylsalicylate the time to occlusive coronary thrombosis was 33 +/- 4 and 32 +/- 6 min, respectively. BM 13.177, in a dose of 5 mg.kg-1, did not modify the time to thrombotic occlusion (35 +/- 7 min), but in six of the eight animals that had received 10 mg.kg-1 BM 13.177, there was no occlusion within 120 min. In the acetylsalicylate-treated animals, collagen-induced platelet aggregation and plasma thromboxane B2 declined by 72 and 82%, respectively. The decreases were 46 and 20%, respectively, with the higher dose of BM 13.177. It is concluded that, in this porcine model of coronary artery thrombosis, the thromboxane antagonist BM 13.177 effectively suppressed formation of occlusive thrombi whereas acetylsalicylate was ineffective at a dose that lowered arterial thromboxane levels.

Animals↗
PubMed1989

Platelet alpha 2-adrenoceptors and adrenergic adipose tissue responsiveness after moderate hypocaloric diet in obese subjects.

Platelet alpha 2-adrenoceptor number was studied in obese subjects treated by a moderate hypocaloric diet (1000-1200 kcal/day = 4200-5000 kg/day) for 21-25 days. Spontaneous lipolysis and adrenergic responsiveness of isolated subcutaneous abdominal adipocytes, collected by a biopsy procedure, were studied before and after treatment on the same subjects. The number of alpha 2-adrenoceptor binding sites (Bmax values) of the platelets was increased after the hypocaloric diet, while there was no change in the equilibrium dissociation constant. Basal lipolytic activity of the adipocytes was increased after the hypocaloric treatment, whereas neither the beta-dependent lipolytic effect of isoproterenol nor the alpha 2-dependent antilipolytic effect of epinephrine were affected. It is concluded that moderate hypocaloric diet induces an up-regulation of platelet alpha 2-adrenoceptors. No modification occurs in alpha 2- and beta-adrenergic responsiveness of the subcutaneous adipocytes. Although alpha 2-adrenergic receptor binding studies on platelets have been widely used as an index for alpha 2-adrenoceptor function in other tissues, it is suggested by this study that platelet alpha 2-adrenoceptors cannot be used for prediction of alpha 2-adrenoceptor function in adipose tissue.

Adipose Tissue↗
PubMed1989

[Asymmetric IgG antibodies. Structural, immunochemical and biological studies].

Studies of our laboratory have shown that the coprecipitating antibodies are IgG molecules which possess an asymmetric structure due to a carbohydrate group present in only one of the Fab regions of the molecule. The combination of the corresponding antibody site with antigen is sterically hindered by the carbohydrate group, and as a consequence, the molecule is functionally univalent. As no aggregation of the antibody takes place, effector immune mechanisms such as complement fixation, phagocytosis, clearance of antigen, etc. are not triggered. However, since nonprecipitating antibodies can firmly combine with antigen, they act in a competitive way when they are mixed with precipitating antibodies of the same specificity. It has been demonstrated that hybridomas synthesize both symmetric and asymmetric molecules indicating that precipitating and nonprecipitating antibodies are elaborated by the same cellular clone. Nonprecipitating antibodies do not precipitate the antigen but they are able to agglutinate sheep red blood cells sensitized with the specific antigen. Because red blood cells of sheep and of many other animal species possess a membrane receptor for aggregated Fc, agglutination of sensitized sheep red cells by nonprecipitating antibodies is a consequence of a mixed mechanism in which one Fab and the Fc fragment of the IgG molecule participate. In animals immunized with soluble antigens, the nonprecipitating antibody represents 10-15% of the total. Higher concentrations have been observed when the inoculated antigen is particulate. In cows infected by B. aortus and in humans infected by T. cruzi, the percentage of nonprecipitating antibody ranges between 30-70% of the total antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

GABAA receptor subunits identified in Paramecium by immunofluorescence confocal microscopy.

The presence of opioid, beta-adrenergic and cholinergic receptors has been demonstrated in ciliated protozoa, but little is known about gamma-aminobutyric acid (GABA) receptors. In this study we have analyzed the distribution of GABA(A)-type receptor subunits in Paramecium. Confocal laser microscopy using antibodies specific for alpha(1)-, alpha(2)-, alpha(3)-, alpha(6)-, beta(2/3)-, gamma(2)-, epsilon-, lambda-, and theta-subunits showed that most receptors are aggregated in clusters and are distributed both on cell surface and in the cytoplasm. The intensity of labelling of the alpha(6)-, beta(2/3)- and gamma(2)-subunits was more intense than the alpha(1)-, epsilon-, and theta-subunits, suggesting that the former are present in higher concentrations than the latter.

Animals↗
PubMed1992

[Thromboxane A2 and prevention of cardiovascular diseases].

Thromboxane A2 (TxA2) is the main arachidonic acid metabolite in human platelets and exhibits two major activities; stimulation of platelet function, including secretion of platelet-derived storage products, e.g., 5-HT, PDGF, and vasoconstriction. Platelet hyperreactivity is typical for advanced stages of atherosclerosis and is paralleled by elevated circulating thromboxane levels. This is the target for TX-antagonistic compounds. Three classes of selective compounds are available: inhibitors of thromboxane synthase, antagonists of thromboxane receptors, and mixed-type agents. Positive experimental data with all of these compounds are available. However, clinical experience is limited and, in general, not convincing. This review discusses possible reasons for that and suggests that, in particular, the use of combined-type agents as antithrombotics may be superior to acetyl-salicylic acid in several forms of ischemic cardiovascular diseases.

Animals↗
PubMed1993

[Oxidized lipoproteins and atherogenesis].

The assumption that the oxidation of lipoproteins plays an eminent role in the development of atherosclerosis is of increasing significance. Our examinations concerned the kinetics of lipid peroxidation of the poly-unsaturated fatty acids in lipoproteins and the existing protection mechanisms by antioxidants, such as vitamin E and carotenoids. Clinical studies proving a correlation of plasma levels and antioxidants, such as vitamin C and E and carotenoids in correlation with cardiovascular disease are cited and discussed. Certain aldehydes originating during lipid peroxidation in LDL modify the protein part of LDL. The consequence of the oxidative modification of LDL is a decreased recognition of LDL by the LDL-receptor and moreover the uptake by macrophages hereby changing to foam cells. Epitopes as developed in oxidatively modified LDL were also shown immunohistochemically in atherosclerotic plaques. Finally a hypothetic scheme is presented how LDL is oxidized in the vessel wall and how it initiates processes resulting in atherosclerosis.

Animals↗
PubMed1985

Cartilage response to mechanical force in high-density chondrocyte cultures.

High-density cultures of chick embryonic chondrocytes were exposed to intermittent compressive force (ICF) of physiologic magnitude for 24 hours. Proteoglycan synthesis was significantly increased in chondrocyte cultures exposed to ICF as compared with control cultures. Similar effects were found in explants of epiphyseal cartilage. Proteoglycans extracted with guanidine-HCl from cultures exposed to ICF aggregated better with hyaluronic acid than did control cultures, as shown by Sepharose 2B gel chromatography. In addition, the amount of non-extractable proteoglycans was increased in ICF cultures. We conclude that ICF not only increases the synthesis of proteoglycans but also improves the aggregating capacity of proteoglycans and the coherence of proteoglycans with other matrix components. High-density cultures of epiphyseal chondrocytes provide a suitable model to study the processes involved in the perception of and the subsequent cellular response to compressive force by cartilage.

Animals↗
PubMed1988

Synthesis and pharmacological evaluation of 5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptane derivatives.

1 alpha,2 beta(5Z),3 beta(1E,3S),4 alpha,5 alpha,6 alpha]-7-[5,6-Epoxy-3- (3-cyclohexyl-3-hydroxy-3-methyl-1-propenyl)-7-oxabicyclo[2.2.1]-hept-2- yl]-5-heptenoic acid (31) and [1 alpha,2 beta(5Z),3 beta(1E,3S),4 alpha,5 alpha,6 alpha]-7-[5,6-epoxy-3-[3-hydroxy-5-(p-hydroxyphenyl)-1- pentenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (37) were found to be selective TxA2 antagonists at the platelet and pulmonary thromboxane receptors. An efficient stereospecific synthesis of these compounds and a series of structural analogues is described. Compounds 31 and 37 both inhibited the bronchoconstriction induced by arachidonic acid in the anesthetized guinea pig.

Adenosine Diphosphate↗