Description:
<jats:p>The concept that oxidation is the major single event underlying the transformation of LDL to a proinflammatory molecule dominates the world literature. An alternative hypothesis on the pathogenesis of atherosclerosis will be presented here. We have found that nonoxidative, enzymatic modification of LDL with ubiquitous enzymes also transforms the molecule to an atherogenic moiety. Enzymatically altered LDL (E‐LDL) shares major properties in common with lipoproteins that have been isolated from atherosclerotic lesions. It activates complement and is recognized by a scavenger receptor on human macrophages, thus inducing foam cell formation. Uptake of E‐LDL is accompanied by induction of MCP−1 synthesis and secretion. In contrast, E‐LDL does not stimulate IL‐1 or TNF‐production and is only a weak inducer of IL‐6. Monoclonal antibodies were produced that recognize neoepitopes on E‐LDL, but that do not react with native or oxidized LDL. With the use of these antibodies, extensive deposition of E‐LDL in very early atherosclerotic lesions was demonstrated. Activated complement components colocalized with E‐LDL, corroborating the concept that subendothelially deposited LDL is enzymatically transformed to a complement activator. The relevance of unhalted complement activation was revealed by the finding that C6‐deftciency markedly protected against development of diet‐induced atherosclerosis in rabbits. Thus, our hypothesis departs from mainstream atherosclerosis research and derives from the recognition that extracellular exposition of free cholesterol by itself confers proinflammatory properties onto LDL. The degrading enzymes probably are present in the extracellular matrix, so the only requirement for atherogenesis to occur is the deposition of large amounts of LDL. Oxidative processes or infections probably play only minor roles, and reduction of LDL plasma levels will predictably represent the single most important prophylactic measure against development and progression of atherosclerosis.</jats:p>