Abstract
Several studies suggest that the complement system is involved in atherogenesis. To further investigate this question, we have studied the ability of native and modified forms of LDL to bind and activate C1, the complex protease that triggers the classical pathway of complement. Unlike native LDL, oxidized (oxLDL) and enzymatically modified (E-LDL) derivatives were both recognized by the C1q subunit of C1, but only E-LDL particles, obtained by sequential treatment with a protease and then with cholesterol esterase, had the ability to trigger C1 activation. Further investigations revealed that C1q recognizes a lipid component of E-LDL. Several approaches, including reconstitution of model lipid vesicles, cosedimentation, and electron microscopy analyses, provided evidence that C1 binding to E-LDL particles is mediated by the C1q globular domain, which senses unesterified fatty acids generated by cholesterol esterase. The potential implications of these findings in atherogenesis are discussed.
Highlights
It is generally accepted that accumulation of low-density lipoproteins (LDLs) in the extracellular matrix of the blood vessels is the starting point of atherogenesis [1]
The various experiments carried out in the past years provide clear experimental evidence that, in contrast to native LDL and oxidized LDL (oxLDL), E-LDL is endowed with the ability to activate C1, the multimolecular protease that triggers the classical
The observation that native LDL particles do not activate C1 is consistent with the fact that these are not recognized by C1q
Summary
It is generally accepted that accumulation of low-density lipoproteins (LDLs) in the extracellular matrix of the blood vessels is the starting point of atherogenesis [1]. That LDL derivatives have the ability to activate the complement system was initially described by Seifert and coworkers, who showed that cholesterol-containing lipid particles isolated from human atherosclerotic lesions activate complement to completion [11]. The ability of native and modified forms of LDL to trigger activation of the C1 complex was tested in vitro by means of a C1 activation assay in the presence of excess C1 inhibitor in order to prevent spontaneous C1 activation [16]. Sequential treatment of native LDL with trypsin and with CEase endowed the resulting E-LDL derivative with the ability to trigger efficient C1 activation [14]. Subsequent modification of trypsin-treated LDL with CEase was clearly a determinant step for generating particles recognized by C1q and exhibiting C1-activating ability. Treatment of native LDL with phospholipase A2 or sphingomyelinase did not yield significant C1 activation
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