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Effects of oxidized low density lipoprotein on endothelin secretion by cultured endothelial cells, monocytes and macrophages

University of British Columbia

Oxidized LDL is present in atherosclerotic lesions and has been shown to have a number of actions of potential importance in atherosclerosis, including stimulation of arterial vasoconstriction. The aim of this study was to determine how oxidized LDL affects endothelin secretion by endothelial cells, monocytes and macrophages. It was found that the effects of oxidized LDL on endothelin production depend on the degree of oxidation of LDL. Extensively oxidized LDL inhibited endothelin expression and secretion from cultured endothelial cells. It also attenuated endothelin release from phorbol ester-activated macrophages. The inhibitory effect on endothelin release required a threshold degree of LDL oxidation as reflected by an increase in absorbance at 234 nm (conjugated diene) of 0.1 per ug LDL protein and a 2 to 3-fold increase in migration distance on agarose gel electrophoresis. There was an apparent toxic effect of extensively oxidized LDL to the cells as judged by inhibition of protein and DNA synthesis. Thus, cytotoxicity of extensively oxidized LDL may at least in part account for the inhibition of endothelin secretion. Native LDL, mildly oxidized LDL or acetyl LDL slightly increased basal endothelin release by endothelial cells and by phorbol ester-activated peripheral blood monocytes. However, only mildly oxidized LDL modestly augmented endothelin production by phorbol ester-activated monocyte-derived macrophages. In general, the stimulatory effects of mildly oxidized LDL on endothelin secretion by cultured cells were of modest degree and/or not specific for mildly oxidized LDL (in that they were also seen with native LDL). For that reason, it is difficult to invoke this effect of mildly oxidized LDL as an important pathophysiological mechanism in vivo. Furthermore, the inhibition of endothelin secretion by extensively oxidized LDL might even be a protective mechanism, in that it would tend to reduce vessel wall tone at sites where oxidized LDL was present, i.e. near atherosclerotic lesions.

Thesis/Dissertation

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2009-02-25

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http://hdl.handle.net/2429/5054

Experimental Medicine

University of British Columbia

UBCV

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