title: Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity.
abstract: The disintegrin-metalloproteinases ADAM10 and ADAM17 mediate the release of several cell signaling molecules and cell adhesion molecules such as vascular endothelial cadherin or L-selectin affecting endothelial permeability and leukocyte transmigration. Dysregulation of ADAM activity may contribute to the pathogenesis of vascular diseases, but the mechanisms underlying the control of ADAM functions are still incompletely understood. Atherosclerosis is characterized by lipid plaque formation and local accumulation of unsaturated free fatty acids (FFA). Here, we show that unsaturated FFA increase ADAM-mediated substrate cleavage. We demonstrate that these alterations are not due to genuine changes in enzyme activity, but correlate with changes in membrane fluidity as revealed by measurement of 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and fluorescence recovery after photobleaching analyses. ELISA and immunoblot experiments conducted with granulocytes, endothelial cells, and keratinocytes revealed rapid increase of ectodomain shedding of ADAM10 and ADAM17 substrates upon membrane fluidization. Large amounts of unsaturated FFA may be liberated from cholesteryl esters in LDL that is entrapped in atherosclerotic lesions. Incubation of cells with thus modified LDL resulted in rapid cleavage of ADAM substrates with corresponding functional consequences on cell proliferation, cell migration, and endothelial permeability, events of high significance in atherogenesis. We propose that FFA represent critical regulators of ADAM function that may assume relevance in many biological settings through their influence on mobility of enzyme and substrate in lipid bilayers.
authors.affiliation: Department of Dermatology, Christian-Albrecht University Kiel, D-24098 Kiel, Germany. kreiss@dermatology.uni-kiel.de
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
authors.forename: Isabell
authors.initials: I
authors.lastname: Cornelsen
authors.forename: Matthias
authors.initials: M
authors.lastname: Husmann
authors.forename: Gerald
authors.initials: G
authors.lastname: Gimpl
authors.forename: Sucharit
authors.initials: S
authors.lastname: Bhakdi
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000401:mortality; D002199:Capillary Permeability / Q000235:genetics; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006098:Granulocytes / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D008560:Membrane Fluidity; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits
chemical_list: D002788:Cholesterol Esters; D005231:Fatty Acids, Unsaturated; D008051:Lipid Bilayers; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human