Regulation of platelet-derived growth factor ligand and receptor gene expression by alpha-thrombin in vascular smooth muscle cells.

Okazaki, Hiroki; Majesky, Mark W.; Harker, Laurence A.; Schwartz, Stephen M.

doi:10.1161/01.res.71.6.1285

Cited by 98 publications

(51 citation statements)

References 43 publications

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“…Additional support for an autocrine mechanism for thrombin-stimulated proliferation has been derived from studies demonstrating increased expression of PDGF-A chain, bFGF, or heparin-binding epidermal growth factor-like growth factor in cultured vascular smooth muscle cells in response to thrombin (33,35,53,54). Thus, these growth factors represent candidate proximal mitogens associated with thrombin-stimulated DNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…The thrombin receptor contains seven hydrophobic (membrane-spanning) domains and belongs to the family of G protein-coupled receptors (10). ␣ -Thrombin binds to this receptor via an anionbinding exosite domain that interacts with the receptor sequence TR [52][53][54][55][56][57][58][59][60] (10,16). Bound thrombin then cleaves a peptide bond on the carboxyl side of Arg 41 exposing a new amino terminus (NH 2 terminus) on the receptor.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Thrombin receptor activation elicits rapid protein tyrosine phosphorylation and stimulation of the raf-1/MAP kinase pathway preceding delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for an obligate autocrine mechanism promoting cell proliferation induced by G-protein-coupled receptor agonist.

Molloy¹,

Pawlowski²,

Taylor³

et al. 1996

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thrombin receptor activation elicits rapid protein tyrosine phosphorylation and stimulation of the raf-1/MAP kinase pathway preceding delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for an obligate autocrine mechanism promoting cell proliferation induced by G-protein-coupled receptor agonist.

Molloy¹,

Pawlowski²,

Taylor³

et al. 1996

J. Clin. Invest.

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“…Autocrine production of PDGF-AA [111][112][113] Autocrine production of basic fibroblast growth factor 114 Autocrine production of epiregulin 115 HBEGF-mediated trans-activation of EGF receptor 41,42 Flavin-containing oxidases 32 Insulin-like growth factor-1 receptor 116 Rho 25 pp60c-src and p21ras 117 ␤ 3 integrins 43 Nuclear factor-B 118 G protein-coupled receptor kinase-2 119 cAMP 120 …”

Section: Table 2 Some Secondary Growth Factors and Signaling Moleculmentioning

confidence: 99%

New Tricks for Old Dogs

Patterson

Stouffer

Madamanchi

et al. 2001

Circulation Research

116

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Abstract-Thrombin is a serine protease that potently activates platelets and catalyzes the conversion of fibrinogen to fibrin. Thrombin also exerts direct effects on vascular cells, such as smooth muscle cells, via interactions with members of the protease-activated receptor family. Evidence in several animal models implicates thrombin-mediated signaling events in the response to injury that typifies vascular lesion formation in atherosclerosis and restenosis. In this review, we examine the activation of protease-activated receptors by thrombin, the downstream signaling events mediated by these receptors, and the physiological role of thrombin in vascular cells and vascular disease. Key Words: atherosclerosis Ⅲ thrombin Ⅲ vascular biology C onceptually, our understanding of the interface between the thrombosis and hemostasis systems, on one hand, and vessel wall biology, on the other hand, is undergoing a gradual evolution. In its earliest formulation, the interface between these two processes was the inert barrier provided by the vascular endothelium; disruption of this barrier was considered the major stimulus to activation of the coagulation cascade. A level of complexity was added by the discovery that platelet proteins (such as platelet-derived growth factor) and hemostatic factors (such as thrombin) have potent activities on vascular biology independently of any coagulation effects. Conversely, we now know that vascular endothelial and smooth muscle cells (SMCs) produce proteins like tissue factor that modulate the coagulation cascade in the absence of endothelial disruption. This situation becomes even more complex when the effects of coagulation factors on cardiovascular development are considered; the recent demonstration that factor V-deficient mice, which cannot generate thrombin, die in utero of vascular defects in the absence of hemorrhage shows how closely these two systems are interrelated. 1 Not only is the interface between coagulation and vessel wall biology not as simple as it was once thought, the boundaries between these two systems can now hardly be defined at all. It is not surprising, then, that the central molecule in blood coagulation, thrombin, also has profound effects on virtually every aspect of vascular wall biology, including regulation of vessel tone; SMC proliferation, differentiation, and migration; vascular development; atherogenesis; and angiogenesis ( Figure 1). The purpose of this review is to take thrombin out of the narrow context of its role in the coagulation cascade and in platelet function (these aspects of thrombin function have been reviewed elsewhere 2,3 ) and to focus on the roles played by thrombin and its vascular receptors in SMC biology and vascular disease. Although to date pharmacologic inhibition of thrombin has yielded mixed results in the treatment and prevention of atherogenesis, a

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“…1 Thrombin can also contribute to the development of graft neointimal hyperplasia through its action as a smooth muscle cell mitogen, a mediator of inflammation, and an agonist for the release of platelet-derived growth factor. [2][3][4][5] Hirudin, a 65-amino acid protein secreted by the salivary glands of the medicinal leech, is a potent and specific inhibitor of thrombin. 6 By blocking both the catalytic site and the anion-binding exosite of thrombin, hirudin inhibits the interaction of thrombin both with fibrinogen and with thrombin receptors that are present on the surface of platelets and vascular cells.…”

Section: Introductionmentioning

confidence: 99%

Retroviral vector-mediated expression of hirudin by human vascular endothelial cells: implications for the design of retroviral vectors expressing biologically active proteins

et al. 1999

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We constructed a hirudin cDNA cassette, HV-1.1, that and mass spectroscopic analysis revealed the presence of encodes mature hirudin variant-1 fused to the signal pepan extra N-terminal serine residue, indicating aberrant tide of human tissue-type plasminogen activator (t-PA).cleavage of the t-PA signal peptide and likely accounting The cassette was subcloned into retroviral vectors and for the diminished activity. We therefore constructed a used to transduce human vascular endothelial cells in vitro.second cDNA cassette, HV-1.2, in which hirudin secretion Hirudin antigen and activity were measured by ELISA and was directed by the signal peptide of human growth horthrombin inhibition assays, respectively. Transduced cells mone. Hirudin expressed from the HV-1.2 cassette had a secreted up to 35 ± 2 ng/10 6 cells/24 h of biologically active specific activity of 13.5 ± 0.2 ATU/ g. Protein sequencing hirudin; expression was stable for at least 7 weeks.and mass spectroscopic analysis demonstrated proper Recombinant hirudin, expressed from the HV-1.1 cassette, cleavage of the growth hormone signal peptide. Thus, we had a specific activity of 7.1 ± 0.2 antithrombin units per achieved high level retrovirus-mediated secretion of biomicrogram (ATU/ g), compared with specific activities of logically active hirudin from endothelial cells in vitro. Use approximately 12 ATU/ g for both native leech hirudin and of these vectors may permit sustained local antagonism of recombinant hirudin produced in yeast. Protein sequencing thrombin activity in vivo.

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Regulation of platelet-derived growth factor ligand and receptor gene expression by alpha-thrombin in vascular smooth muscle cells.

Cited by 98 publications

References 43 publications

New Tricks for Old Dogs

Retroviral vector-mediated expression of hirudin by human vascular endothelial cells: implications for the design of retroviral vectors expressing biologically active proteins

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