1. Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation
- Author
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Jenni Huusko, Hongxia Zhao, Sami Rissanen, Matti Javanainen, Ilpo Vattulainen, Mohamad Navab, Petri T. Kovanen, Katariina Öörni, Seppo Ylä-Herttuala, Alan M. Fogelman, Su Duy Nguyen, Annukka M. Kivelä, Institute of Biotechnology, Hongxia Zhao / Principal Investigator, Medicum, Clinicum, and Mitochondrial Morphogenesis
- Subjects
conformation ,CHOLESTEROL EFFLUX ,ATHEROGENIC LIPOPROTEINS ,030204 cardiovascular system & hematology ,Sphingomyelin phosphodiesterase ,Biochemistry ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Biomimetics ,E-NULL MICE ,HUMAN PLASMA ,Lipid bilayer ,Research Articles ,Aorta ,0303 health sciences ,Research Support, Non-U.S. Gov't ,SUBENDOTHELIAL RETENTION ,apolipoprotein B-100 ,Lipoproteins, LDL ,Membrane ,Sphingomyelin Phosphodiesterase ,OXIDIZED LIPIDS ,Low-density lipoprotein ,Apolipoprotein B-100 ,lipids (amino acids, peptides, and proteins) ,proteoglycans ,Sphingomyelin ,retention ,Lipolysis ,LOW-DENSITY-LIPOPROTEIN ,interaction ,QD415-436 ,AMPHIPATHIC HELICAL PEPTIDES ,03 medical and health sciences ,Hydrolysis ,HUMAN AORTIC PROTEOGLYCANS ,Journal Article ,Humans ,030304 developmental biology ,Apolipoprotein A-I ,Proteoglycan binding ,Cell Biology ,chemistry ,FORCE-FIELD ,1182 Biochemistry, cell and molecular biology ,atherosclerosis ,Peptides ,low density lipoprotein - 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-modifi ed 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.
- Published
- 2015
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