In early atherogenesis, subendothelial retention of lipidic droplets is associated with an inflammatory response-to-injury, culminating in the formation of foam cells and plaque. Low density lipoprotein (LDL) is the main constituent of subendothelial lipidic droplets. LDL can be sketched as an inner lipidic core surrounded by a phospholipid monolayer, with the protein (apoB-100) wrapped around the particles’ surface and partly seeping into the phospholipid monolayer and the inner cholesterol core. We found that in a naturally occurring subpopulation of LDL (electronegative LDL-), the apoB-100 is misfolded and is capable of triggering the formation of aggregated, amyloid-like LDL structures. LDL- can be produced in human plasma by secretory phospholipases A2. Both protein misfolding and LDL amyloids can well represent modifications able to transform this cholesterol carrier into a trigger for a response-to-injury in the artery wall. Furthermore, by using Small Angle X-ray Scattering we furnish further evidences that the hormone 17-b-estradiol (E2) binds to a single highly specific site in apoB-100 and stabilizes its structure, even if the formation of LDL- is not altered by E2 binding. This results in an increased ellipticity of apoB- 100, an overall volume shrinkage with modifications both in the outer shell and lipidic core, and an increased resistance to structural and conformational loss. Notably, also the formation of LDL amyloid aggregates is hindered by E2. Our findings converge to a picture where a possible explanation of the beneficial effect of E2 in the protection against the vascular response-to-injury can find its mechanism. In addition, our results add arguments to the stringent lipid-protein structural interplay in LDL, with modifications in lipids being paralleled with apoB- 100 structural and functional modifications, and vice versa.
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