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Kinetic analysis of thermal stability of human low‐density lipoproteins: A model for LDL fusion in atherogenesis
Author(s) -
Lu Mengxiao,
Jayaraman Shobini,
Gantz Donald L,
Herscovitz Haya,
Gursky Olga
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1208.8
Subject(s) - chemistry , fusion , denaturation (fissile materials) , thermostability , size exclusion chromatography , kinetics , cholesterol , biophysics , thermal stability , biochemistry , chromatography , nuclear chemistry , enzyme , organic chemistry , biology , philosophy , linguistics , physics , quantum mechanics
Fusion of modified LDL (Bad Cholesterol) in the arterial wall is an important underexplored event in early atherosclerosis. Previously we showed that thermal denaturation mimics LDL remodeling and revealed kinetic origin of LDL stability. Here we report the first quantitative analysis of LDL thermostability. Turbidity data show sigmoidal kinetics of LDL heat denaturation which is unique among lipoproteins. High activation energy of LDL denaturation indicates disruption of extensive packing interactions. Size‐exclusion chromatography, gel electrophoresis and electron microscopy suggest that LDL dimerization is a novel early step in LDL fusion. Ion‐exchange chromatography suggests that a subset of electronegative LDL is responsible for dimerization. LDL fusion accelerates at pH<7, which may contribute to LDL retention in acidic atherosclerotic lesions. Fusion also accelerates upon increasing LDL concentration, which likely contributes to atherogenesis. LDL stability decreases with increasing particle size, indicating that the pro‐atherogenic properties of small dense LDL do not result from their enhanced fusion. Our work provides the first kinetic approach to measuring LDL stability and suggests that lipid‐lowering therapies that reduce LDL concentration but increase the particle size may have opposite effects on LDL fusion. This work was supported by NIH grants GM067260 and HL026335.