Staff Profile:Dr David Leake

Name::
Position / Job Title:
Reader in the Biochemistry of Atherosclerosis
Responsibilities:
Programme Adviser for Biomedical Sciences
Areas of Interest:

The oxidation of low density lipoprotein (LDL) is believed by many to be important in atherogenesis. The oxidised LDL hypothesis proposes that cells in the arterial wall oxidise LDL in the interstitial fluid and then take it up rapidly, leading to the formation of foam cells. Two key problems with the conventional oxidised LDL hypothesis are that the oxidation is inhibited by low concentrations of interstitial fluid and that large clinical trials have shown no protection by antioxidants against cardiovascular disease. To account for these problems, we hypothesised that LDL might be nonoxidatively modified and aggregated by enzymes, such as sphingomyelinase, secretory phospholipase A2s or proteases, in the interstitial fluid of atherosclerotic lesions. It would then be rapidly phagocytosed by macrophages, delivered to lysosomes and oxidised within these organelles. We showed that after taking up aggregated LDL macrophages, including human monocyte-derived macrophages, generated ceroid in their lysosomes. (Ceroid is a polymerised product of lipid oxidation found within foam cells.) Furthermore, 7-ketocholesterol, one of the main products of LDL oxidation, was detected by HPLC after macrophages were treated with acetylated LDL, which is also rapidly endocytosed. The oxidation was inhibited by chloroquine, which increases the pH of lysosomes, and by an iron chelator. Others have demonstrated that foam cells in human atherosclerotic lesions contain catalytically active iron in their lysosomes. Iron can oxidise LDL effectively at the lysosomal pH of about 4.5, but not at pH 7.4, as measured by spectrophotometry.

We have recently shown that an antioxidant, which concentrates in lysosomes by several orders of magnitude, greatly inhibits LDL oxidation by FeSO4 (5 ┬ÁM) at pH 4.5, as measured by spectrophotometry. LDL aggregated by incubation with sphingomyelinase was rapidly taken up by macrophages and became extensively oxidised in their lysosomes, as indicated by the accumulation of ceroid. A low concentration of the antioxidant inhibited the production of ceroid by about 80%. This concentration is well below what can be achieved in human plasma. The extent of atherosclerotic lesions in the aortic root and arch of LDL receptor-deficient mice fed a Western diet was significantly reduced by the antioxidant. The antioxidant did not affect plasma lipid concentrations. These results support the hypothesis that the lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide therapies for this disease.

Research groups / Centres:
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Contact Details

Email:
d.s.leake@reading.ac.uk
Telephone:
+44 (0) 118 378 7062

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