title: Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation.
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.
authors: Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.
authors: Su Duy
authors: SD
authors: Nguyen
authors: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors: Matti
authors: M
authors: Javanainen
authors: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors: Sami
authors: S
authors: Rissanen
authors: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors: Hongxia
authors: H
authors: Zhao
authors: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors: Jenni
authors: J
authors: Huusko
authors: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors: Annukka M
authors: AM
authors: Kivelä
authors: A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland Science Service Center, Kuopio University Hospital, Kuopio, Finland.
authors: Seppo
authors: S
authors: Ylä-Herttuala
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors: Mohamad
authors: M
authors: Navab
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors: Alan M
authors: AM
authors: Fogelman
authors: Department of Physics, Tampere University of Technology, Tampere, Finland MEMPHYS-Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark.
authors: Ilpo
authors: I
authors: Vattulainen
authors: Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.
authors: Petri T
authors: PT
authors: Kovanen
authors: Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.
authors: Katariina
authors: K
authors: Öörni
mesh_terms: D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000494:pharmacology*; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D032701:Biomimetics; D006801:Humans; D008066:Lipolysis / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; D008077:Lipoproteins, LDL; D010455:Peptides; C582295:apolipoprotein A-I mimetic peptide 4F; D013108:Sphingomyelin Phosphodiesterase
keywords: apolipoprotein B-100; atherosclerosis; conformation; interaction; low density lipoprotein; proteoglycans; retention