Submitted on August 3, 2007
Revised on December 21, 2007
Accepted on January 16, 2008
A moderate reduction in extracellular pH protects macrophages against apoptosis induced by oxidized low density lipoprotein
Andrew B. Gerry and David S. Leake
School of Biological Sciences (AMS), University of Reading, Reading, Berkshire RG6 6AJ
Corresponding Author: a.b.gerry{at}rdg.ac.uk
We investigated the effect of pH on macrophage apoptosis induced by oxidised low density lipoprotein, as human atherosclerotic lesions have regions of low pH. Hydroperoxide-rich and oxysterol-rich low density lipoprotein (LDL) caused 38% and 74% apoptosis of J774 macrophages, respectively, at 24h, as measured by the externalisation 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 oxidised LDL, by 61% and 46%, respectively (P<0.001). These data were confirmed by semi-quantitative analysis of cytochrome c release from mitochondria. Lowering the extracellular pH to 7.0 reduced the uptake of hydroperoxide-rich and oxysterol-rich 125I-labelled LDL by 82% and 42%, respectively, and cell surface binding of oxysterol-rich LDL by 31%. This may explain the reduced apoptosis. Additionally, low pH did not affect oxidised LDL-induced apoptosis of human monocytes, which do not possess scavenger receptors for oxidised LDL, 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 oxidised LDL and reduce macrophage apoptosis, thus affecting lesion progression.
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