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.
Keywords: Amyloid, electronegative low density lipoprotein, oxidized low density lipoprotein, phospholipase A2, subendothelial droplets, 17-β-estradiol.
Current Medicinal Chemistry
Title:Misfolding of Apoprotein B-100, LDL Aggregation and 17-β -estradiol in Atherogenesis
Volume: 21 Issue: 20
Author(s): R. Brunelli, M. De Spirito, G. Mei, M. Papi, G. Perrone, C. Stefanutti and T. Parasassi
Affiliation:
Keywords: Amyloid, electronegative low density lipoprotein, oxidized low density lipoprotein, phospholipase A2, subendothelial droplets, 17-β-estradiol.
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.
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Cite this article as:
Brunelli R., Spirito De M., Mei G., Papi M., Perrone G., Stefanutti C. and Parasassi T., Misfolding of Apoprotein B-100, LDL Aggregation and 17-β -estradiol in Atherogenesis, Current Medicinal Chemistry 2014; 21 (20) . https://dx.doi.org/10.2174/0929867321666140120114944
DOI https://dx.doi.org/10.2174/0929867321666140120114944 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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