Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation |
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Authors: | Su Duy Nguyen Matti Javanainen Sami Rissanen Hongxia Zhao Jenni Huusko Annukka M Kivel? Seppo Yl?-Herttuala Mohamad Navab Alan M Fogelman Ilpo Vattulainen Petri T Kovanen Katariina ??rni |
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Institution: | 2. Department of Physics, Tampere University of Technology, Tampere, Finland;4. Institute of Biotechnology, University of Helsinki, Helsinki, Finland;11. Science Service Center, Kuopio University Hospital, Kuopio, Finland;8. Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA |
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Abstract: | Lipolytic modification of LDL particles by SMase generates LDL aggregates with a strong affinity for human arterial proteoglycans and may so enhance LDL retention in the arterial wall. Here, we evaluated the effects of apoA-I mimetic peptide 4F on structural and functional properties of the SMase-modified LDL particles. LDL particles with and without 4F were incubated with SMase, after which their aggregation, structure, and proteoglycan binding were analyzed. At a molar ratio of L-4F to apoB-100 of 2.5 to 20:1, 4F dose-dependently inhibited SMase-induced LDL aggregation. At a molar ratio of 20:1, SMase-induced aggregation was fully blocked. Binding of 4F to LDL particles inhibited SMase-induced hydrolysis of LDL by 10% and prevented SMase-induced LDL aggregation. In addition, the binding of the SMase-modified LDL particles to human aortic proteoglycans was dose-dependently inhibited by pretreating LDL with 4F. The 4F stabilized apoB-100 conformation and inhibited SMase-induced conformational changes of apoB-100. Molecular dynamic simulations showed that upon binding to protein-free LDL surface, 4F locally alters membrane order and fluidity and induces structural changes to the lipid layer. Collectively, 4F stabilizes LDL particles by preventing the SMase-induced conformational changes in apoB-100 and so blocks SMase-induced LDL aggregation and the resulting increase in LDL retention. |
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Keywords: | low density lipoprotein apolipoprotein B-100 proteoglycans retention atherosclerosis conformation interaction |
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