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Figure 6 Illustration of Atherosclerosis as a Protein Quality Disease

In the initial phase of cardiovascular risk factor exposure, compensatory up-regulation of chaperones and the ubiquitin-proteasome system (UPS) prevents the overwhelming intracellular accumulation of damaged and dysfunctional proteins. The UPS activity also contributes to the classical activation pathway of nuclear factor kappa-B and thereby to inflammation and cell proliferation. With the formation and growth of a metabolically active atherosclerotic plaque, there is further production of misfolded and damaged proteins in the progression phase. Once the classical protein quality mechanisms are overwhelmed and fail, these dysfunctional proteins accumulate (and aggregate) and autophagy remains the final clearance pathway. The accumulating proteins can undergo further oxidation, ubiquitination, and cross-linking. As yet another unique characteristic, beta-pleated sheets can be formed and hence amyloid fibrils via the intermediate steps of pre-amyloid oligomers and protofibrils. In addition to intracellular proteins, proteins in the extracellular matrix can undergo conformational changes. For instance, oxidation and phospholipid hydrolysis of low-density lipoprotein (LDL) produces oxidatively modified and electronegative particles with unfolding of the apolipoprotein components (electron microscopic images used with permission of Elsevier Science [35]). The generation of amyloid-like structures in this process serves as a potent "key" to the uptake of these modified LDLs by macrophages via scavenger receptors (37). Recognition of amyloid-like fibrils by CD36 (and conceivably the receptor for advanced glycation end-products) leads to the production of reactive oxygen species, chemokines, and cytokines, which contributes further to the atherosclerotic disease process, including its complication phase.