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)

G-proteins are transducing proteins that couple a large number of membrane-bound receptors to a variety of intracellular effector systems. Pertussis toxin ADP-ribosylates certain G-proteins causing inhibition of their function. In porcine coronary arteries, pertussis toxin inhibited the endothelium-dependent relaxations evoked by alpha-2-adrenergic or serotonergic receptor stimulation, and by aggregating platelets or thrombin. Relaxations to nitric oxide and endothelium-dependent relaxations to bradykinin, adenosine diphosphate or A23187 were unaffected by the toxin. Therefore, certain endothelium-dependent relaxations are mediated by activation of a pertussis toxin-sensitive G-protein in the endothelial cells, most likely Gi-protein. In porcine coronary arteries with regenerated endothelium (following in vivo denudation), the endothelium-dependent relaxations caused by the pertussis toxin-sensitive stimuli were reduced and were not further affected by pertussis toxin. Relaxations to the other stimuli were not altered by the regeneration process and were still not affected by the toxin. In regenerating endothelial cells there may be a selective impairment of the G-protein-dependent mechanism for releasing EDRF, which may predispose the blood vessel to vasospasm or the initiation of vascular disease.
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PMID:G-proteins and endothelial responses. 212 22

Growth of vascular smooth muscle cells (VSMC) plays an important role in the pathogenesis of atherosclerosis and hypertension. Lysophosphatidic acid (LPA), a natural phospholipid is thought to be an important VSMC mitogen and has recently been suggested to play an important role in the development of vascular disease. In the present study, we describe the effects of LPA on intracellular signalling pathways in VSMC. LPA (5 micrograms/ml) induced an increase of cytosolic free calcium concentration ([Ca2+]i) in the presence and absence of extracellular Ca2+ and markedly stimulated the Na+/H+ exchanger. LPA dose-dependently caused a stimulation of the 42-kDa mitogen-activated protein kinase (MAP kinase) isoform with a maximum at 5 min. Also, LPA induced a 5-fold increase in [3H]thymidine incorporation into cell DNA above the basal value, as well as a 42% increase in cell number. Pretreatment of VSMC with pertussis toxin (PTX) (100 ng/ml) for 24 h markedly blunted the LPA-dependent intracellular signalling transduction including the increase in [Ca2+]i, activation of the Na+/H+ exchanger, activation of MAP kinase and the increase in cell DNA synthesis. These findings demonstrate that the effects of LPA on intracellular signalling transduction pathway as well as on VSMC growth are mediated by PTX-sensitive guanosine triphosphate (GTP) binding protein (Gi protein).
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PMID:Lysophosphatidic acid and intracellular signalling in vascular smooth muscle cells. 912 56

The role of the cAMP signaling pathway in vascular calcification was investigated using calcifying vascular cells (CVC) derived from primary aortic medial cell cultures. We previously showed that CVC have fibroblastic morphology and express several osteoblastic differentiation markers. After confluency, they aggregate into cellular condensations, which later mature into nodules where mineralization is localized. Here, we investigated the effects of cAMP on CVC differentiation because it plays a role in both osteoblastic differentiation and vascular disease. Dibutyryl-cAMP or forskolin treatment of CVC for 3 days induced osteoblast-like "cuboidal" morphology, inhibited proliferation, and enhanced alkaline phosphatase activity, all early markers of osteoblastic differentiation. Isobutylmethylxanthine and cholera toxin had the same effects. Treatment of CVC with pertussis toxin, however, did not induce the morphological change or increase alkaline phosphatase activity, although it inhibited CVC proliferation to a similar extent. cAMP also increased type I procollagen production and gene expression of matrix gamma-carboxyglutamic acid protein, recently shown to play a role in in vivo vascular calcification. cAMP inhibited the expression of osteopontin but did not affect the expression of osteocalcin and core binding factor. Prolonged cAMP treatment enhanced matrix calcium-mineral incorporation but inhibited the condensations resulting in diffuse mineralization throughout the monolayer of cells. Treatment of CVC with a protein kinase A-specific inhibitor, KT5720, inhibited alkaline phosphatase activity and mineralization during spontaneous CVC differentiation. These results suggest that the cAMP pathway promotes in vitro vascular calcification by enhancing osteoblast-like differentiation of CVC.
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PMID:cAMP stimulates osteoblast-like differentiation of calcifying vascular cells. Potential signaling pathway for vascular calcification. 951 56

Vascular smooth muscle cell (VSMC) proliferation is a prominent feature of the atherosclerotic process occurring after endothelial injury. A vascular wall kallikrein-kinin system has been described. The contribution of this system to vascular disease is undefined. In the present study we characterized the signal transduction pathway leading to mitogen-activated protein kinase (MAPK) activation in response to bradykinin (BK) in VSMC. Addition of 10(-10)-10(-7) M BK to VSMC resulted in a rapid and concentration-dependent increase in tyrosine phosphorylation of several 144- to 40-kDa proteins. This effect of BK was abolished by the B(2)-kinin receptor antagonist HOE-140, but not by the B(1)-kinin receptor antagonist des-Arg(9)-Leu(8)-BK. Immunoprecipitation with anti-phosphotyrosine antibodies followed by immunoblot revealed that 10(-9) M BK induced tyrosine phosphorylation of focal adhesion kinase (p125(FAK)). BK (10(-8) M) promoted the association of p60(src) with the adapter protein growth factor receptor binding protein-2 and also induced a significant increase in MAPK activity. Pertussis and cholera toxins did not inhibit BK-induced MAPK tyrosine phosphorylation. Protein kinase C downregulation by phorbol 12-myristate 13-acetate and/or inhibitors to protein kinase C, p60(src) kinase, and MAPK kinase inhibited BK-induced MAPK tyrosine phosphorylation. These findings provide evidence that activation of the B(2)-kinin receptor in VSMC leads to generation of multiple second messengers that converge to activate MAPK. The activation of this crucial kinase by BK provides a strong rationale to investigate the mitogenic actions of BK on VSMC proliferation in disease states of vascular injury.
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PMID:Mechanisms of MAPK activation by bradykinin in vascular smooth muscle cells. 1044 1

Recent studies have shown that proteoglycans play an important role in the development of vascular disease and renal failure. In this study, the effects of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimulation on glycosaminoglycan and proteoglycan core protein synthesis in vascular smooth muscle cells (VSMC) were examined. Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in (3)H-glucosamine/(35)S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan. The effects of AngII were inhibited by the epidermal growth factor receptor inhibitor, AG1478, and the mitagen-activated protein kinase kinase inhibitor, PD98059, but not the protein kinase C inhibitors, chelerythrine and staurosporine. AngII treatment also resulted in significant increases in the mRNA of the core proteins, versican, biglycan, and perlecan. The effects of AT2 receptor stimulation were examined by retroviral transfection of VSMC with the AT2 receptor. Stimulation of the AT2 receptor in these VSMC-AT2 cells resulted in a significant (1.3-fold) increase in proteoglycan synthesis, which was abolished by the AT2 receptor antagonist, PD123319, and attenuated by pretreatment with pertussis toxin. These results implicate both AT1 and AT2 receptors in the regulation of proteoglycan synthesis and suggest the involvement of epidermal growth factor receptor-dependent tyrosine kinase pathways and G alpha i/o-mediated mechanisms in the effects of the two receptors.
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PMID:Regulation of vascular proteoglycan synthesis by angiotensin II type 1 and type 2 receptors. 1172 29

Thrombospondin-1 is a large matricellular protein that acts as a pleiotropic growth factor for human vascular smooth muscle cells, and may play a role in the progression of vascular disease. Although we have previously demonstrated the dependence of both thrombospondin-1-stimulated cell chemotaxis and proliferation on tyrosine kinases, the receptor mechanisms involved remain obscure. This investigation aims to determine the nature of the receptor(s) involved in the cellular responses to thrombospondin-1. Cellular signals were identified by western blotting following cell stimulation, while cellular responses were assessed by measuring DNA synthesis and chemotaxis. These data demonstrate that thrombospondin-1-induced cell chemotaxis can be inhibited by a peptide containing the Arg-Gly-Asp motif, a function-blocking alpha(v)beta(3) antibody, a function-blocking integrin-associated protein (IAP) antibody and pertussis toxin, while thrombospondin-1-stimulated DNA synthesis is inhibited by a function-blocking alpha(3)beta(1) antibody. Similarly the Arg-Gly-Asp-containing peptide inhibits tyrosine phosphorylation of focal adhesion kinase and the p85 regulatory subunit of phosphatidylinositol 3-kinase, but does not significantly affect tyrosine phosphorylation, or activation, of extracellular-regulated kinase. These data suggest that soluble thrombospondin-1 interacts with human vascular smooth muscle cells via two independent and separable receptor-binding sites, to differentially stimulate cell chemotaxis and DNA synthesis.
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PMID:Thrombospondin-1 differentially induces chemotaxis and DNA synthesis of human venous smooth muscle cells at the receptor-binding level. 1237 66

Fractalkine (also known as CX3CL1), a CX3C chemokine, activates and attracts monocytes/macrophages to the site of injury/inflammation. It binds to CX3C receptor 1 (CX3CR1), a pertussis toxin-sensitive G-protein-coupled receptor. In smooth muscle cells (SMCs), fractalkine is induced by proinflammatory cytokines [tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)], which may mediate monocyte adhesion to SMCs. However, the mechanisms underlying its induction are unknown. In addition, it is unlear whether SMCs express CX3CR1. TNF-alpha activated nuclear factor kappaB (NF-kappaB) and induced fractalkine and CX3CR1 expression in a time-dependent manner in rat aortic SMCs. Transient transfections with dominant-negative (dn) inhibitory kappaB (IkappaB)-alpha, dnIkappaB-beta, dnIkappaB kinase (IKK)-gamma, kinase-dead (kd) NF-kappaB-inducing kinase (NIK) and kdIKK-beta, or pretreatment with wortmannin, Akt inhibitor, pyrrolidinecarbodithioc acid ammonium salt ('PDTC') or MG-132, significantly attenuated TNF-alpha-induced fractalkine and CX3CR1 expression. Furthermore, expression of dn TNF-alpha-receptor-associated factor 2 (TRAF2), but not dnTRAF6, inhibited TNF-alpha signal transduction. Pretreatment with pertussis toxin or neutralizing anti-CX3CR1 antibodies attenuated TNF-alpha-induced fractalkine expression, indicating that fractalkine autoregulation plays a role in TNF-alpha-induced sustained fractalkine expression. Fractalkine induced its own expression, via pertussis toxin-sensitive G-proteins, phosphoinositide 3-kinase (PI 3-kinase), phosphoinositide-dependent kinase 1 (PDK1), Akt, NIK, IKK and NF-kappaB activation, and induced SMC cell-cell adhesion and cellular proliferation. Taken together, our results demonstrate that TNF-alpha induces the expression of fractalkine and CX3CR1 in rat aortic SMCs and that this induction is mediated by NF-kappaB activation. We also show that fractalkine induces its own expression, which is mediated by the PI 3-kinase/PDK1/Akt/NIK/IKK/NF-kappaB signalling pathway. More importantly, fractalkine increased cell-cell adhesion and aortic SMC proliferation, indicating a role in initiation and progression of atherosclerotic vascular disease.
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PMID:Fractalkine (CX3CL1) stimulated by nuclear factor kappaB (NF-kappaB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway. 1272 61

A hallmark of vascular smooth muscle cells (VSMCs) is their dynamic ability to assemble and disassemble contractile proteins into sarcomeric units depending upon their phenotypic state. This phenotypic plasticity plays an important role during vascular development and in obstructive vascular disease. Previously, we showed that the Elastin gene product, tropoelastin, activates myofibrillar organization of VSMCs. Recently, others have suggested that elastin does not have a direct signaling role but rather binds to and alters the interactions of other matrix proteins with their cognate receptors or disrupts the binding of growth factors and cytokines. In contrast, we provide evidence that tropoelastin directly regulates contractile organization of VSMCs. First, we show that a discrete domain within tropoelastin, VGVAPG, induces myofibrillogenesis in a time- and dose-dependent fashion. We confirm specificity using a closely related control peptide that fails to stimulate actin stress fiber formation. Second, the activity of VGVAPG is not affected by the presence or absence of other serum or matrix components. Third, both the elastin hexapeptide and tropoelastin stimulate actin polymerization through a common pertussis toxin-sensitive G protein pathway that activates RhoA-GTPase and results in the conversion of G to F actin. Collectively, these data support a model whereby the elastin gene product, signaling through the VGVAPG domain, directly induces VSMC myofibrillogenesis.
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PMID:Elastin induces myofibrillogenesis via a specific domain, VGVAPG. 1461 88

CXCL16, a recently discovered transmembrane chemokine, is expressed in human aortic smooth muscle cell (ASMC). It facilitates uptake of low density lipoproteins by macrophages, resulting in foam cell formation. However, it is not known whether ASMC express CXCR6, the receptor for CXCL16, or whether CXCL16 affects ASMC biology. To dissect the biological and signal transduction pathways elicited by CXCL16, human aortic smooth muscle cells (HASMC) were treated with pharmacological inhibitors or transiently transfected with pathway-specific dominant-negative or kinase-dead expression vectors prior to the addition of CXCL16. HASMC expressed CXCR6 at basal conditions. Exposure of HASMC to CXCL16 increased NF-kappa B DNA binding activity, induced kappa B-driven luciferase activity, and up-regulated tumor necrosis factor-alpha expression in an NF-kappa B-dependent manner. However, treatment with pertussis toxin (G(i) inhibitor), wortmannin or LY294002 (phosphatidylinositol 3-kinase (PI3K inhibitors)), or Akt inhibitor or overexpression of dominant-negative (dn) PI3K gamma, dnPDK-1, kinase-dead (kd) Akt, kdIKK-beta, dnIKK-gamma, dnI kappa B-alpha, or dnI kappa B-beta significantly attenuated CXCL16-induced NF-kappa B activation. Furthermore, CXCL16 increased cell-cell adhesion and induced cellular proliferation in an NF-kappa B-dependent manner. In conclusion, CXCL16 is a potent and direct activator of NF-kappaB and induces kappa B-dependent proinflammatory gene transcription. CXCL16-mediated NF-kappa B activation occurred via heterotrimeric G proteins, PI3K, PDK-1, Akt, and I kappa B kinase (IKK). CXCL16 induced I kappa B phosphorylation and degradation. Most importantly, CXCL16 increased cell-cell adhesion and induced kappa B-dependent ASMC proliferation, indicating that CXCL16 may play an important role in the development and progression of atherosclerotic vascular disease.
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PMID:CXCL16 signals via Gi, phosphatidylinositol 3-kinase, Akt, I kappa B kinase, and nuclear factor-kappa B and induces cell-cell adhesion and aortic smooth muscle cell proliferation. 1462 85

Adenosine is a vascular endothelial cell mitogen, but anti-mitogenic for aortic smooth muscle cells and fibroblasts when acting via the A2B adenosine receptor. However, we show that adenosine increases porcine coronary artery smooth muscle cell (CASMC) number, cellular DNA content, protein synthesis, and PCNA staining. RT-PCR analysis indicates that porcine CASMC express A1, A2A, A3, and barely detectable levels of A2B receptor mRNAs. The mitogenic effect of adenosine is mimicked by NECA, CCPA, and R-PIA, but not by CGS21680and 2-Cl-IB-MECA, and is inhibited by DPCPX, indicating a prominent role for the A1 receptor. This interpretation is supported by the finding that adenosine- and CCPA-induced DNA synthesis is significantly inhibited by pertussis toxin, but substantially potentiated by PD81723, an allosteric enhancer of the A1 receptor. When a cDNA encoding the porcine A1 receptor was cloned and expressed in COS-1 cells, A1 receptor pharmacology is confirmed. Anti-sense oligonucleotides to the cloned sequence dramatically suppress the mitogenic effect of adenosine and CCPA. Conversely, over-expression of the cloned A1 receptor in CASMC increases adenosine- and CCPA-induced DNA synthesis. Furthermore, stimulation with adenosine or CCPA of intact coronary arteries in an organ culture model of vascular disease increases cellular DNA synthesis, which was abolished by DPCPX. We conclude that adenosine acts as a novel mitogen in porcine CASMC that express the A1 adenosine receptor, possibly contributing to the development of coronary artery disease.
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PMID:Novel mitogenic effect of adenosine on coronary artery smooth muscle cells: role for the A1 adenosine receptor. 1583 18


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