Misfolding of apoprotein B-100, LDL aggregation and 17-β -estradiol in atherogenesis.

Abstract

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.

• Authors: R Brunelli, M De Spirito, G Mei, M Papi, G Perrone, C Stefanutti, T Parasassi
• Journal: Current medicinal chemistry (Curr Med Chem) Vol. 21 Issue 20 Pg. 2276-83 ( 2014) ISSN: 1875-533X [Electronic] United Arab Emirates
• PMID: 24438526 (Publication Type: Journal Article, Review)

Chemical References

• Apolipoproteins B
• Lipoproteins, LDL
• oxidized low density lipoprotein
• Estradiol

Topics

• Apolipoproteins B (chemistry, metabolism)
• Atherosclerosis (metabolism)
• Estradiol (metabolism)
• Humans
• Lipoproteins, LDL (chemistry, metabolism, ultrastructure)
• Oxidation-Reduction
• Protein Folding