title: Mechanistic roles of lipoprotein lipase and sphingomyelinase in low density lipoprotein aggregation.
abstract: The initiation of atherosclerosis involves retention of colloidal atherogenic lipoproteins, primarily low density lipoprotein (LDL), in the arterial intima. This retention occurs when LDL binds to smooth muscle cell extracellular matrix (SMC ECM), and is enhanced by lipoprotein lipase (LpL) and sphingomyelinase (Smase). Here we use a fluorescence assay and dynamic light scattering to study the individual and combined effects of these two enzymes on LDL aggregation. Our results show: (1) LpL is self-sufficient to induce LDL aggregation with aggregate sizes up to ~400 nm; (2) Smase induces LDL aggregation due to generation of ceramide and subsequent hydrophobic interactions; (3) Smase hydrolysis of LpL-induced LDL aggregates does not cause further aggregation and results in a ~3-fold diminished production of ceramide, while LpL treatment of Smase-induced aggregates does enhance aggregation; (4) The simultaneous addition of LpL and Smase causes increased variability in aggregation with final sizes ranging from 50 to 110 nm. Our data suggest a new proatherogenic function for LpL, namely, bridging between LDL particles causing their aggregation and consequently enhanced retention by SMC ECM. The mechanism of LpL-and-Smase-mediated LDL aggregation and binding to SMC ECM provides specific points of intervention to design novel effective antiatherogenic therapeutics.
authors.affiliation: Department of Chemical and Biological Engineering, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA. waltm@dental.upenn.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Walters
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wrenn
mesh_terms: D007700:Kinetics; D008071:Lipoprotein Lipase / Q000737:chemistry / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D010316:Particle Size; D013108:Sphingomyelin Phosphodiesterase / Q000737:chemistry / Q000378:metabolism*; D013499:Surface Properties
chemical_list: D008077:Lipoproteins, LDL; D008071:Lipoprotein Lipase; D013108:Sphingomyelin Phosphodiesterase