Summary

Atherosclerosis is widely regarded as a chronic inflammatorydisease that develops as a consequence of entrapment of lowdensity lipoprotein (LDL) in the arterial intima. Native LDLlacks inflammatory properties, so the lipoprotein must undergobiochemical alterations in order to become atherogenic.Modification is commonly regarded as being dangerous becauseit bestows inflammatory properties onto the lipoprotein. Mostcurrent models consider oxidation to be the decisive modifyingevent. Here, we submit a different concept for discussion. Wepropose that modification of tissue-entrapped LDL is requiredbecause it enables the lipoprotein to signal to the immunesystem and effect its own removal. Oxidation would be toohaphazard to fulfill this function. We summarize the evidenceindicating that modification occurs through the action of ubiquitoushydrolytic enzymes. Enzymatically remodeled LDL binds C-reactive protein. C-reactive protein bound to remod-eledLDL not only activates complement but also regulates it byinhibiting activation of the terminal complement cascade.Simultaneously, epitopes are exposed to enable the lipoproteinto be recognized and taken up by macrophages. The high densitylipoprotein-dependent reverse transport pathway concludesthe sequence of events that clear tissues of cholesterolin a non-inflammatory manner very similar to what has beendescribed for the removal of apoptotic cells. It is proposed thatthese physiological processes occur throughout life withoutharm, pathology evolving only when the machinery suffersoverload. Detrimental effects are then evoked primarily by theunreigned activation of complement, macrophages, and othereffectors of the immune system in the lesions.