title: Sphingomyelinase, an enzyme implicated in atherogenesis, is present in atherosclerotic lesions and binds to specific components of the subendothelial extracellular matrix.
abstract: Atherosclerotic lesions contain an extracellular sphingomyelinase (SMase) activity that hydrolyzes the sphingomyelin of subendothelial low density lipoprotein (LDL). This SMase activity may promote atherosclerosis by enhancing subendothelial LDL retention and aggregation, foam cell formation, and possibly other atherogenic processes. The results of recent cell-culture studies have led to the hypothesis that a specific molecule called secretory SMase (S-SMase) is responsible for the SMase activity known to be in lesions, although its presence in atheromata had not been examined directly. Herein we provide immunohistochemical and biochemical support for this hypothesis. First, 2 different antibodies against S-SMase detected extracellular immunoreactive protein in the intima of mouse, rabbit, and human atherosclerotic lesions. Much of this material in lesions appeared in association with the subendothelial matrix. Second, binding studies in vitro demonstrated that (125)I-S-SMase adheres to the extracellular matrix of cultured aortic smooth muscle and endothelial cells, specifically to the laminin and collagen components. Third, in its bound state, S-SMase retains substantial enzymatic activity against lipoprotein substrates. Overall, these data support the hypothesis that S-SMase is an extracellular arterial wall SMase that contributes to the hydrolysis of the sphingomyelin of subendothelial LDL. S-SMase may therefore be an important participant in atherogenesis through local enzymatic effects that stimulate subendothelial retention and aggregation of atherogenic lipoproteins.
authors.affiliation: Departments of Medicine and Anatomy & Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: S
authors.initials: S
authors.lastname: Marathe
authors.forename: G
authors.initials: G
authors.lastname: Kuriakose
authors.forename: K J
authors.initials: KJ
authors.lastname: Williams
authors.forename: I
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D001161:Arteriosclerosis / Q000201:enzymology* / Q000209:etiology; D002417:Cattle; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000378:metabolism / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D003871:Dermatan Sulfate / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007457:Iodine Radioisotopes; D007797:Laminin / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D011485:Protein Binding / Q000502:physiology; D011817:Rabbits; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000032:analysis / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D007457:Iodine Radioisotopes; D007797:Laminin; D003871:Dermatan Sulfate; D012710:Serum Albumin, Bovine; D006493:Heparin; D002809:Chondroitin Sulfates; D003094:Collagen; D013108:Sphingomyelin Phosphodiesterase