Heparin Potentiates Endothelial Gell Growth Factor Stimulation of Plasminogen Activator Synthesis by Diploid Human Lung Fibroblasts

Rappaport, Ruth; Ronchetti-Blume, Marlene; Vogel, Robert L.; Hung, Paul P.

doi:10.1055/s-0038-1647526

Cited by 11 publications

(3 citation statements)

References 17 publications

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“…A possible mechanism for this increase in tPA concentration could be a heparin induced release of tPA from binding sites on the surface of endothelial cells (47). Alternatively, heparin might also induce tPA synthesis (48). Plasma FFA/triacylglycerol infusion, however, had no specific effect on plasma tPA.…”

Section: Discussionmentioning

confidence: 94%

Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man

Krebs¹,

Geiger²,

Polak³

et al. 2003

Thromb Haemost

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Increased plasma plasminogen activator inhibitor-1 (PAI-1) has been implicated in the development of vascular disease. In type 2 diabetes mellitus high PAI-1 levels are associated with increased plasma concentrations of free fatty acids (FFA) and triacylglycerol indicating an association or a causal relationship. To answer that question, the effect of FFA/triacylglycerol on plasma PAI-1 was examined. Ten healthy male volunteers were studied for 6 h during infusion of triacylglycerol [1.5 ml/min]/heparin [0.2 IU/(kg.min)] (LIP; n=10), saline only (SAL; n=10), and saline/heparin (HEP; n=5). Plasma insulin concentrations were kept constant at approximately 35 pmol/l by intravenous somatostatin-insulin infusions and there was no significant change in plasma glucose levels during any of the study protocols. LIP increased plasma triacylglycerol and FFA approximately 3- (p < 0.001) and approximately 8- (p < 0.000001) fold, respectively, within 90 min. Baseline plasma PAI-1 measured by a bio-immunoassay was similar in HEP (11.4 +/- 2.8 ng/ml), SAL (16.6 +/- 3.6 ng/ml), and LIP studies (15.2 +/- 3.4 ng/ml). Since studies were initiated in the morning, PAI-1 decreased (p < 0.025) over time following its normal diurnal variation to 6.4 +/- 2.0 ng/ml and 4.0 +/- 2.4 ng/ml at 360 min in SAL and HEP, respectively. During LIP, however, PAI-1 increased to approximately 2.6 fold higher levels than during SAL at 360 min (16.4 +/- 4.0 ng/ml, p < 0.01). While tissue plasminogen activator (tPA) and adipsin, an adipocyte derived protease, were unaffected by LIP, changes in soluble vascular cell adhesion molecule-1 (sVCAM-1) were significantly correlated (p = 0.02) with those seen for PAI-1. This suggests that hyperlipidemia independent of insulin and plasma glucose levels stimulates vascular tissue and in turn might induce an increase in plasma PAI-1. PAI-1 then could contribute to the development of atherothrombotic vascular disease.

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Section: Discussionmentioning

confidence: 94%

Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man

Krebs¹,

Geiger²,

Polak³

et al. 2003

Thromb Haemost

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“…BS-I lectin (30 .g of isolectin B4 per ml; this and other immunoreagents were from Vector Laboratories) was added to hydrogen peroxide-and serum-blocked sections followed by overnight incubation with affinity-purified goat anti-BS-I primary antibody (1.0 ,ug/ml). Affinity-purified biotinylated rabbit antigoat secondary antibody (7.5 kg/ml) was added followed 1 hr later by avidin linked to horseradish peroxidase (Vectastain ABC peroxidase kit).…”

mentioning

confidence: 99%

Acidic fibroblast growth factor promotes vascular repair.

Bjornsson

Dryjski

Tluczek

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

110

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Intravascular injury to arteries can result in thickening of the intimal smooth muscle layer adjacent to the lumen by migration and proliferation of cells from the underlying medial smooth muscle layer accompanied by deposition of extracellular matrix. This pathological response, which decreases lumen diameter, might, in part, be the result of the access of smooth muscle cells to plasma and platelet-derived growth factors as a consequence of denudation of the overlying confluent monolayer of vascular endothelial cells. Injured rat carotid arteries were treated by i.v. administration of acidic fibroblast growth factor, a heparin-binding protein that is chemotactic and mitogenic for vascular endothelial cells. The growth factor treatment resulted in dose-dependent inhibition of intimal thickening with parallel promotion of endothelial regeneration over the injured area. Therefore, acidic fibroblast growth factor might be efficacious in the prevention of restenosis caused by intimal thickening following angioplasty in humans.Arterial architecture consists of an inner nonthrombogenic monolayer of vascular endothelial cells residing on a basement membrane covering thin intimal and thicker underlying medial layers of smooth muscle. Response to extensive arterial endothelial injury is characterized by migration and proliferation of medial smooth muscle cells into the intima, perhaps mediated by plasma-and platelet-derived growth factors, with the accumulation of extracellular matrix resulting in thickening of the intimal layer thereby decreasing vascular lumen diameter (1-3).In animal models of limited arterial injury, spontaneous endothelial regeneration results in the cessation of both smooth muscle cell proliferation and intimal thickening (4)(5)(6). However, since vascular endothelium appears to have a limited ability to spontaneously repopulate denuded areas, repair of larger intravascular injuries can be incomplete (7). Therefore, specific mitogenic and chemotactic stimulation of vascular endothelial cells might promote arterial repair.Several vascular endothelial cell mitogens have been identified, including platelet-derived endothelial cell growth factor (8), vascular endothelial cell growth factor (9-11), and many (12, 13), but not all (14), members of the fibroblast growth factor (FGF) family. The heparin-binding FGF family is composed of seven known homologous members. Acidic FGF (aFGF), one of the more extensively characterized family members, is both mitogenic (15) and chemotactic (16) for vascular endothelial cells in vitro and promotes blood vessel growth, or angiogenesis, in vivo (15,17,18). We describe the results of a series of experiments demonstrating that aFGF also both promotes repair of experimentally damaged rat arterial endothelium and inhibits the accompanying pathological intimal thickening. Adjusted for body weight, the i.v. infusion rates of aFGF and animal group sizes, n, were 2.9 (n = 3), 26 (n = 5), 130 (n = 8), 270 (n = 9), and 870 (n = 5) pg'kg-1 hr-1 and 2.6 (n = 9) and 27 (n ...

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“…As discussed previously, this action is enhanced by heparin on lung diploid human fibroblasts (107). Heparin also potentiates the mitotic stimulatory action of ECGF on endothelial cells (116).…”

Section: Growthmentioning

confidence: 67%

Heparin, Heparinoids, Synthetic Polyanions, and Anionic Dyes

Regelson

1991

ACS Symposium Series

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Review of native heparin action provides new applica tions for synthetic polyanions. Furor over dextran sulfate or suramin, anionic dyes as anti-AIDS or anti-tumor drugs forgets the past history of polyanions: As physicochemical combinants, reverse transcriptase inhibitors and immunoadjuvants. This goes back to Ehrlich and anionic dyes, S. S. Cohen and heparin, ethylene maleic anhydride copolymers, and the macroanionic tungstates and heteropolymolybdates. Unfortunately, in this AIDS era, vaccine enhancing action of the polycarboxylate polymers Diveema (MVE, pyran copolymer) is still ignored. Their clinically effective anti-tumor potential requires intraperitoneal not intravenous use. Preclinical experience with newer sulfated native glycosaminoglycan heparin fractions should re-evaluate the place of synthetic polyanions for anti coagulant, lipolytic (anti-atherosclerosis action), anti -inflammatory effects and DNA modulation. Inhibition of angio genesis and smooth muscle proliferation via modulation of cytokines as well as oral absorption and endothelial localization provides new roles for polyanions of clinical value.In recent years, there has been a veritable explosion of interest in both native heparin or heparin related, glycosaminoglycans; synthetic polyanions, or anionic dyes. It is the purpose of this review to discuss pertinent observations regarding the structural and physiologic actions of these negatively charged polymers because of new interest in their clinical application, independent of uses involving surface modification of implantable polymers.Since Jaques' (1.2) and Engelberg's (3.4) last reviews, Lane & Lindhal (5) have provided a new text that focuses on heparin related proteoglycans where there are excellent sections discussing structure and function (6), but the text is focussed on the naturally derived compounds and completely ignores the water soluble synthetic polyanions whose development stemmed from these native compounds.

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Heparin Potentiates Endothelial Gell Growth Factor Stimulation of Plasminogen Activator Synthesis by Diploid Human Lung Fibroblasts

Cited by 11 publications

References 17 publications

Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man

Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man

Acidic fibroblast growth factor promotes vascular repair.

Heparin, Heparinoids, Synthetic Polyanions, and Anionic Dyes

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