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Effects of the heparin-mimicking compound RG-13577 on lipoprotein lipase and on lipase mediated binding of LDL to cells
Umeå University, Faculty of Medicine, Medical Biosciences.
Umeå University, Faculty of Medicine, Medical Biosciences.
Umeå University, Faculty of Medicine, Medical Biosciences.
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2001 (English)In: Atherosclerosis, ISSN 0021-9150, Vol. 157, no 1, 13-21 p.Article in journal (Refereed) Published
Abstract [en]

Lipoprotein lipase (LPL) has high affinity for heparin and heparin-like compounds. In vivo the enzyme is attached to heparan sulfate proteoglycans on the endothelium of capillaries and larger blood vessels. The enzyme is released from these sites after intravenous injection of heparin. One has here investigated the effects of RG-13577 on LPL, both after intravenous injection to rats and under cell culture conditions. RG-13577 is a heparin-mimicking compound known to prevent angiogenesis by interference with binding of growth factors to cells. It has therefore been considered for use in cancer therapy as well as for prevention of atherosclerosis and restenosis. It was found that intravenously injected RG-13577 released both LPL and hepatic lipase (HL) to the blood. Binding of LPL in extrahepatic tissues was prevented and clearance of radiolabeled LPL from the circulation was delayed. Furthermore, RG-13577 released LPL from extracellular matrix (ECM) produced by endothelial cells and from THP-1 monocyte-derived macrophages. Lipase-mediated binding and uptake of human LDL in these cells was also prevented by RG-13577. Thus, in the test systems RG-13577 had the same effects as heparin, but on a molar basis RG-13577 was in all cases less effective.

Place, publisher, year, edition, pages
2001. Vol. 157, no 1, 13-21 p.
URN: urn:nbn:se:umu:diva-4621DOI: 10.1016/S0021-9150(00)00652-3PubMedID: 11427199OAI: diva2:143803
Available from: 2005-08-18 Created: 2005-08-18Bibliographically approved
In thesis
1. Aspects on lipoprotein lipase and atherosclerosis
Open this publication in new window or tab >>Aspects on lipoprotein lipase and atherosclerosis
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lipoprotein lipase (LPL) hydrolyses blood lipids at the vascular endothelium. This action makes fatty acids available for tissue metabolic requirements. LPL is anchored to the endothelium by electrostatic forces and may act as a bridge connecting lipoproteins to cell surfaces. Clusters of positively charged amino acid residues in LPL interact with anionic groups on oligosaccharides covering the cell surfaces. Heparin competes with cell surface oligosaccharides for binding to LPL. Interaction of LPL with soluble and cell surface- ound oligosaccharides influences the activity and catabolism of the enzyme. LPL has a dual role in the development of atherosclerosis. Hydrolysis of lipoproteins by LPL contributes to clearance of lipids from plasma, resulting in an anti-atherogenic lipid profile. On the other hand, trough its bridging function, LPL contributes to lipoprotein retention at the endothelium and in the connective tissue of the artery wall. Furthermore LPL may stimulate uptake of lipoproteins in cells, converting them to foam cells. In this way LPL is considered to be proatherogenic.

We have investigated the effects caused by a synthetic heparin analogue, RG-13577, developed for treatment of tumors by anti-angiogenesis theraphy (Paper I) and by heparin (Paper II) on the turnover and biological role of LPL. The variation of LPL activity in kidney among animal species was studied in Paper III. Localization of LPL in healthy and atherosclerotic human arteries in relation to two other heparin-binding proteins (extracellular superoxide dismutase and apolipoprotein B) was studied in Paper IV.

54 p.
National Category
urn:nbn:se:umu:diva-564 (URN)91-7305-8998 (ISBN)
Public defence
2005-09-07, sal E04, NUS, 09:00 (English)
Available from: 2005-08-18 Created: 2005-08-18 Last updated: 2009-10-13Bibliographically approved

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