[An alternative hypothesis of the pathogenesis of atherosclerosis].

Why LDL entrapped in the subendothelium should trigger events leading to chronic inflammation and to arterial wall injury is a major enigma of modern medicine. Oxidation of LDL in vitro renders the molecule potentially atherogenic, and the concept that oxidation is the major single event underlying the transformation of LDL to a proinflammatory molecule dominates the world literature. Here, an alternative hypothesis on the pathogenesis of atherosclerosis will be presented. We have found that non-oxidative, enzymatic modification of LDL with ubiquitous enzymes (protease + cholesterol esterase + neuraminidase) 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 via the alternative pathway and is recognized by a scavenger receptor on human macrophages, thus inducing foam cell formation. Uptake of E-LDL is accompanied by potent 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 at the earliest stages in lesion development. The pathogenetic relevance of unhalted complement activation in atherogenesis was demonstrated with the use of C6-deficient rabbits. It was found that C6-deficiency markedly protected against development of diet-induced atherosclerosis in the experimental animals. In sum, our hypothesis departs from the mainstream of atherosclerosis research and derives from the recognition that extracellular exposition of free cholesterol in LDL-particles by itself confers pro-inflammatory properties onto the lipoprotein molecule. We believe that the degrading enzymes are ubiquitously 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.