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Journal of Lipid Research, Vol. 49, 782-789, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

A moderate reduction in extracellular pH protects macrophages against apoptosis induced by oxidized low density lipoprotein

Andrew B. Gerry and David S. Leake¹

Cardiovascular Research Group, Biomolecular Sciences Section, School of Biological Sciences, University of Reading, Reading, Berkshire RG6 6AJ, United Kingdom

Published, JLR Papers in Press, January 17, 2008.

¹ To whom correspondence should be addressed. e-mail: d.s.leake{at}reading.ac.uk

We investigated the effect of pH on macrophage apoptosis induced by oxidized low density lipoprotein (OxLDL), as human atherosclerotic lesions have regions of low pH. Hydroperoxide-rich and oxysterol-rich LDL caused 38% and 74% apoptosis of J774 macrophages, respectively, at 24 h, as measured by the externalization of phosphatidylserine. Native LDL, however, did not cause apoptosis. Reducing the pH of the culture medium from 7.4 to 7.0 inhibited apoptosis induced by hydroperoxide-rich or oxysterol-rich OxLDL by 61% and 46%, respectively (P < 0.001). These data were confirmed by semiquantitative analysis of cytochrome c release from mitochondria. Decreasing the extracellular pH to 7.0 reduced the uptake of hydroperoxide-rich and oxysterol-rich ¹²⁵I-labeled LDL by 82% and 42%, respectively, and reduced cell surface binding of oxysterol-rich LDL by 31%. This may explain the reduced apoptosis. Additionally, low pH did not affect OxLDL-induced apoptosis of human monocytes, which do not possess scavenger receptors for OxLDL, but reduced apoptosis of human monocyte-derived macrophages, which do possess them. Our investigations suggest that the presence of areas of low pH within atherosclerotic lesions may reduce the uptake of OxLDL and reduce macrophage apoptosis, thus affecting lesion progression.

Supplementary key words atherosclerosis • inflammation • monocyte • necrosis • scavenger receptor

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