Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombospondin-1 (THBS1) is a large extracellular matrix glycoprotein that affects vasculature systems such as platelet activation, angiogenesis, and wound healing. Increases in THBS1 expression have been liked to disease states including tumor progression, atherosclerosis, and arthritis. The present study focuses on the effects of thrombin activation of the G-protein-coupled, protease-activated receptor-1 (PAR-1) on THBS1 gene expression in the microvascular endothelium. Thrombin-induced changes in gene expression were characterized by microarray analysis of approximately 11,000 different human genes in human microvascular endothelial cells (HMEC-1). Thrombin induced the expression of a set of at least 65 genes including THBS1. Changes in THBS1 mRNA correlated with an increase in the extracellular THBS1 protein concentration. The PAR-1-specific agonist peptide (TFLLRNK-PDK) mimicked thrombin stimulation of THBS1 expression, suggesting that thrombin signaling is through PAR-1. Further studies showed THBS1 expression was sensitive to pertussis toxin and protein kinase C inhibition indicating G(i/o)- and G(q)-mediated pathways. THBS1 up-regulation was also confirmed in human umbilical vein endothelial cells stimulated with thrombin. Analysis of the promoter region of THBS1 and other genes of similar expression profile identified from the microarray predicted an EBOX/EGRF transcription model. Expression of members of each family, MYC and EGR1, respectively, correlated with THBS1 expression. These results suggest thrombin formed at sites of vascular injury increases THBS1 expression into the extracellular matrix via activation of a PAR-1, G(i/o), G(q), EBOX/EGRF-signaling cascade, elucidating regulatory points that may play a role in increased THBS1 expression in disease states.
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PMID:Thrombin modulates the expression of a set of genes including thrombospondin-1 in human microvascular endothelial cells. 1581 47

The aim of this study was to assess the effect of ZR on the growth of cultured human hepatic myofibroblast cells (hMF). The zedoary (Zedoariae Rhizoma) made from the dried rhizome of Curcuma zedoaria Roscoe is an herbal drug used as an aromatic stomachic. The plant is a perennial herb which is natively distributed throughout Korea and is a traditional Korean herbal medicine. Zedoariae rhizoma is a bioactive traditional medicine with anti-tumor, anti-atherosclerosis, anti-inflammation, and growth-regulating properties. During the course of liver fibrogenesis, hMF, mostly derived from hepatic stellate cells, proliferate and synthesize excessive amounts of extracellular matrix components. To evaluate the antiproliferative effect of a traditional herbal medicine, Zedoariae rhizoma water extracts (ZR) was examined on the growth inhibition of hMF since proliferation of hMF is known to be central for the development of fibrosis during liver injury, and factors that may limit their growth are potential antifibrotic agents. The aim of this study was to test the effects of ZR on the proliferation in cultured hMF. hMF were obtained by outgrowth from human liver explants. ZR markedly reduced serum driven cell proliferation, as assessed by nuclear autoradiography experiments and measurement of actual cell growth. Growth inhibition was totally reversed after removal of the ZR. ZR potently inhibited hMF growth (IC50 = 8.5 microg/ml), in a pertussis toxin-insensitive manner. Analysis of the mechanisms involved in growth inhibition revealed that ZR rapidly increased prostaglandin E2 production and in turn cAMP, which inhibited hMF proliferation, did not affect cAMP levels. Production of cAMP by ZR was abolished by NS-398, a selective inhibitor of cycloxygenase (COX)-2. Also, ZR potently induced COX-2 protein expression. Blocking COX-2 by NS-398 blunted the antiproliferative effect of ZR. We conclude that ZR inhibits proliferation of hMF, probably via an intracellular mechanism, through early COX-2-dependent release of prostaglandin E2 and cAMP, and delayed COX-2 induction. Our results indicated a novel role for ZR as a growth inhibitory mediator and pointed out its potential involvement in the negative regulation of liver fibrogenesis. The results that ZR exhibits potent antiproliferative and antifibrogenic effects toward hMF, indicated that ZR might have therapeutic implications in chronic liver disease.
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PMID:The inhibitory effect of a Korean herbal medicine, Zedoariae rhizoma, on growth of cultured human hepatic myofibroblast cells. 1596 8

We present evidence for a novel TLR2 function in transmodulating the adhesive activities of human monocytes in response to the fimbriae of Porphyromonas gingivalis, a pathogen implicated in chronic periodontitis and atherosclerosis. Monocyte recruitment into the subendothelium is a crucial step in atherosclerosis, and we investigated the role of P. gingivalis fimbriae in stimulating monocyte adhesion to endothelial cells and transendothelial migration. Fimbriae induced CD11b/CD18-dependent adhesion of human monocytes or mouse macrophages to endothelial receptor ICAM-1; these activities were inhibited by TLR2 blockade or deficiency or by pharmacological inhibitors of PI3K. Moreover, this inducible adhesive activity was sensitive to the action of Clostridium difficile toxin B, but was not affected by Clostridium botulinum C3 exoenzyme, pertussis toxin, or cholera toxin. Accordingly, we subsequently showed through the use of dominant negative signaling mutants of small GTPases, that Rac1 mediates the ability of fimbria-stimulated monocytes to bind ICAM-1. A dominant negative mutant of Rac1 also inhibited the lipid kinase activity of PI3K suggesting that Rac1 acts upstream of PI3K in this proadhesive pathway. Furthermore, fimbriae stimulated monocyte adhesion to HUVEC and transmigration across HUVEC monolayers; both activities required TLR2 and Rac1 signaling and were dependent upon ICAM-1 and the high-affinity state of CD11b/CD18. P. gingivalis-stimulated monocytes displayed enhanced transendothelial migration compared with monocytes stimulated with nonfimbriated isogenic mutants. Thus, P. gingivalis fimbriae activate a novel proadhesive pathway in human monocytes, involving TLR2, Rac1, PI3K, and CD11b/CD18, which may constitute a mechanistic basis linking P. gingivalis to inflammatory atherosclerotic processes.
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PMID:TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae. 1675 12

The migration of vascular smooth muscle cells (SMCs) is a hallmark of the pathogenesis of atherosclerosis and restenosis after angioplasty. Plasma low-density lipoprotein (LDL), but not high-density lipoprotein (HDL), induced the migration of human coronary artery SMCs (CASMCs). Among bioactive lipids postulated to be present in LDL, lysophosphatidic acid (LPA) appreciably mimicked the LDL action. In fact, the LDL-induced migration was markedly inhibited by pertussis toxin, an LPA receptor antagonist Ki-16425, and a small interfering RNA (siRNA) targeted for LPA(1) receptors. Moreover, LDL contains a higher amount of LPA than HDL does. HDL markedly inhibited LPA- and platelet-derived growth factor (PDGF)-induced migration, and sphingosine 1-phosphate (S1P), the content of which is about fourfold higher in HDL than in LDL, mimicked the HDL action. The inhibitory actions of HDL and S1P were suppressed by S1P(2) receptor-specific siRNA. On the other hand, the degradation of the LPA component of LDL by monoglyceride lipase or the antagonism of LPA receptors by Ki-16425 allowed LDL to inhibit the PDGF-induced migration. The inhibitory effect of LDL was again suppressed by S1P(2) receptor-specific siRNA. In conclusion, LPA/LPA(1) receptors and S1P/S1P(2) receptors mediate the stimulatory and inhibitory migration response to LDL and HDL, respectively. The balance of not only the content of LPA and S1P in lipoproteins but also the signaling activity between LPA(1) and S1P(2) receptors in the cells may be critical in determining whether the lipoprotein is a positive or negative regulator of CASMC migration.
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PMID:Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells. 1723 47

Apoptosis is an important mechanism involved in regulating the number of macrophages present at sites of inflammation. Several lines of evidence indicate that blocking macrophage apoptosis can increase atherosclerosis. We previously reported that oxidized LDL can inhibit apoptosis in cultured bone marrow-derived macrophages. We used pertussis toxin (PTX) to test whether G protein coupled receptors are activated by oxLDL. PTX is a bacterial toxin that inhibits Gi activation by ADP-ribosylating the alpha subunit of Gi, preventing the subunit from interacting with receptors. Unexpectedly, we found that PTX by itself selectively blocks macrophage apoptosis in a dose-dependent manner. PTX acts in part by inhibiting acid sphingomyelinase activity which in turn prevents generation of ceramide, which is required for macrophage apoptosis. A Gi activator peptide, mastoparan, increased ceramide levels in macrophage and induced apoptosis, but pre-treatment with PTX partially overrode mastoparan-induced apoptosis. The anti-apoptotic effect of PTX was found to require ADP-ribosylation. PTX failed to prevent A-SMase activation or apoptosis in macrophages lacking TLR4. The anti-apoptotic effect of PTX involved the same signaling pathways as those of oxidized LDL, in that both inhibited acid sphingomyelinase, and activated the phosphoinositide 3 kinase (PI3K)/protein kinase B (PKB) pathway which leads to nuclear localization of the transcription factor NFkappaB and up-regulation of Bcl-XL. These results indicate that Gi proteins, TLR4, A-SMase and the PI3K/PKB pathway are crucial components for regulation of macrophage apoptosis.
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PMID:Pertussis toxin promotes macrophage survival through inhibition of acid sphingomyelinase and activation of the phosphoinositide 3-kinase/protein kinase B pathway. 1752 84

Sphingosine 1-phosphate (S1P) is a lipid mediator that exerts potent and diverse biological effects on several cardiovascular cells. We investigated the effect of S1P on interleukin (IL)-1beta-induced nitric oxide (NO) production and inducible NO synthase (iNOS) expression in rat vascular smooth muscle cells (VSMCs). S1P inhibited NO production at concentrations higher than 0.1 muM; this was associated with the inhibition of iNOS protein and mRNA expression. S1P also inhibited IL-1beta-induced GTP cyclohydrolase I (GTPCH) mRNA expression. Pertussis toxin (PTX) partially attenuated the inhibitory effects of S1P on NO production and iNOS protein induction, whereas it completely blocked the inhibitory effects on iNOS and GTPCH mRNA expression. S1P inhibited iNOS expression in Ca(2+)-depleted conditions; PTX did not modify this effect. The Rho kinase inhibitor Y 27632 partially but significantly attenuated the inhibitory effect of S1P on iNOS expression in Ca(2+)-depleted condition but did not affect it in the presence of Ca(2+). S1P significantly inhibited IL-1beta-induced persistent activation of extracellular signal-regulated kinase (ERK) but had no effect in Ca(2+)-depleted conditions. Thus, S1P inhibits IL-1beta induction of NO production and iNOS expression in rat VSMCs through multiple mechanisms involving both PTX-sensitive and -insensitive G proteins coupled to S1P receptors. Furthermore, Ca(2+)-dependent ERK inhibition and Ca(2+)-independent Rho kinase activation might be involved in the inhibitory mechanism of iNOS expression. Through its action on NO production by VSMCs, S1P may play an important role in the progression of local vascular injury associated with thrombosis, atherosclerosis, and hypertension.
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PMID:Sphingosine 1-phosphate inhibits nitric oxide production induced by interleukin-1beta in rat vascular smooth muscle cells. 1817 8

The chemokine CXCL4/platelet factor-4 is released by activated platelets in micromolar concentrations and is a chemoattractant for leukocytes via an unidentified receptor. Recently, a variant of the human chemokine receptor CXCR3 (CXCR3-B) was described, which transduced apoptotic but not chemotactic signals in microvascular endothelial cells following exposure to high concentrations of CXCL4. Here, we show that CXCL4 can induce intracellular calcium release and the migration of activated human T lymphocytes. CXCL4-induced chemotaxis of T lymphocytes was inhibited by a CXCR3 antagonist and pretreatment of cells with pertussis toxin (PTX), suggestive of CXCR3-mediated G-protein signaling via Galphai-sensitive subunits. Specific binding by T lymphocytes of the CXCR3 ligand CXCL10 was not effectively competed by CXCL4, suggesting that the two are allotopic ligands. We subsequently used expression systems to dissect the potential roles of each CXCR3 isoform in mediating CXCL4 function. Transient expression of the CXCR3-A and CXCR3-B isoforms in the murine pre-B cell L1.2 produced cells that migrated in response to CXCL4 in a manner sensitive to PTX and a CXCR3 antagonist. Binding of radiolabeled CXCL4 to L1.2 CXCR3 transfectants was of low affinity and appeared to be mediated chiefly by glycosaminoglycans (GAGs), as no specific CXCL4 binding was observed in GAG-deficient 745-Chinese hamster ovary cells stably expressing CXCR3. We suggest that following platelet activation, the CXCR3/CXCL4 axis may play a role in T lymphocyte recruitment and the subsequent amplification of inflammation observed in diseases such as atherosclerosis. In such a setting, antagonism of the CXCR3/CXCL4 axis may represent a useful, therapeutic intervention.
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PMID:CXCL4-induced migration of activated T lymphocytes is mediated by the chemokine receptor CXCR3. 1817 62

Lysophosphatidic acid (LPA) is a low-molecular-weight lysophospholipid enriched in platelets and mildly oxidized low-density lipoprotein (OxLDL). It is suggested that LPA is involved in atherosclerosis, and our previous studies showed that LPA regulates inflammation in multiple cell types. The main aim of this study was to investigate the effects of LPA on the uptake of OxLDL by mouse J774A.1 macrophages. We observed that LPA upregulated fluorescence-labeled DiI-OxLDL uptake in J774A.1 cells. Meanwhile, expression of the class A scavenger receptor (SR-A), a receptor for modified LDL, was also enhanced. Furthermore, pertussis toxin (PTx) or Ki16425 significantly abolished LPA's effects, indicating that G(i) and LPA(3) are involved in OxLDL uptake and SR-A expression. Of most importance, the LPA-induced OxLDL uptake could be inhibited when cells were incubated with a functional blocking antibody of SR-A. Our results suggest that LPA-enhanced OxLDL uptake is mediated via LPA(3)-G(i) activation and subsequent SR-A expression.
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PMID:Lysophosphatidic acid-induced oxidized low-density lipoprotein uptake is class A scavenger receptor-dependent in macrophages. 1858 71

The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDHF-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive G(i) (e.g. responses to serotonin and thrombin) and pertussis toxin-insensitive G(q) (e.g. adenosine diphosphate and bradykinin) coupling proteins. The release of NO by the endothelial cell can be up-regulated (e.g. by oestrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and causing endothelium-dependent hyperpolarizations), endothelial cells also can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factor (EDCF). Most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells. EDCF-mediated responses are exacerbated when the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients.
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PMID:Endothelial dysfunction and vascular disease. 1922 Feb 4

The endothelium causes relaxations of the underlying vascular smooth muscle, by releasing nitric oxide (NO). The endothelial cells also can evoke hyperpolarization of the vascular smooth muscle cells (endothelium-dependent hyperpolarizations, endothelium-derived hyperpolarizing factors-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi and pertussis toxin-insensitive Gq coupling proteins. The endothelial release of NO is reduced in diabetes and hypertension. Arteries covered with regenerated endothelium lose the pertussis-toxin sensitive pathway for NO-release. This dysfunction favors vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. Endothelial cells also release endothelium-derived contracting factors (EDCF). Most endothelium-dependent contractions are mediated by vasoconstrictor prostanoids (endoperoxides and prostacyclin), which activate thromboxane-prostanoid (TP)-receptors of the underlying vascular smooth muscle cells. EDCF-mediated responses are augmented by aging, hypertension and diabetes. Thus, endothelial dysfunction is the first step toward coronary arteriosclerosis.
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PMID:Endothelial dysfunction: the first step toward coronary arteriosclerosis. 1922 3


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