The long quest for a missing mechanistic rationale accounting for the correlation between plasma cholesterol levels
and cardiovascular disease (CVD) has been focused on various possible modifications of low density lipoprotein (LDL), turning
this physiological cholesterol carrier into a damaging agent able to trigger atherogenesis and later the onset of the disease.
In addition to the debated oxidized LDL (oxLDL), a modified LDL with a misfolded apoprotein B-100, called electronegative
LDL(-) for its negative charge due to an increased amount of free fatty acids, is commonly present in plasma. LDL(-) is
generated by the action of secretory calcium dependent phospholipase A2. LDL(-) primes LDL aggregation and amyloid
formation according to mechanisms very similar to those observed in other misfolding diseases. The LDL particle aggregates
recall the structure and size of the subendothelial lipid droplets described in early atherogenesis and elicit a powerful inflammatory
response. The use of 17-β-estradiol (E2) confirmed that the suggested atherogenicity of LDL (-) is mostly dependent
on the misfolded character of its apoprotein. E2 binding to the apoprotein of native LDL, through a specific and saturable receptor,
inhibits misfolding phenomenon despite an unaffected production of LDL (-) by phospholipase A2, ultimately preventing
LDL aggregation. The apoprotein misfolding in LDL(-) emerges as a possible significant trigger mechanism of
atherogenesis. Potential implications for the development of novel therapeutic approaches might be hypothesized in perspective.
The existing evidence is discussed and reported in this review.
Keywords: Amyloid, electronegative low density lipoprotein, oxidized low density lipoprotein, phospholipase A2, subendothelial
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