Malondialdehyde binding to proteins dramatically alters fibroblast functions.
The regulation of cell metabolism by the surrounding environment is deeply altered by the posttranslational nonenzymatic modifications of extracellular proteins that occur throughout lifespan in vivo and modify their structural and functional properties. Among them are protein adducts formed by components generated from oxidative processes, such as malondialdehyde (MDA). We have investigated here the effects of MDA-binding to proteins on cultured fibroblast functions. Type I collagen and/or serum proteins were incubated with 0-100 mM MDA for 3 h before use in fibroblast cultures. In tridimensional lattice cultures, MDA-treated collagen inhibited the contracting activity of fibroblasts. A similar inhibition of lattice contraction was reproduced by the addition of MDA-treated serum to the culture medium. In monolayer cultures, the addition of MDA-modified serum proteins completely inhibited fibroblast multiplication without effect on initial adhesion steps. MDA-modified proteins decreased the proliferative capacities of cells, strongly altered cell cycle progression by blocking passage to G2/M phases, and induced apoptotic features in fibroblasts. Our results show, for the first time, that MDA-modified proteins are potentially as deleterious as free MDA, and could be involved in aging as well as in degenerative complications of diseases with increased oxidative stress such as diabetes mellitus or atherosclerosis.
Rittié
Laure
L
Laboratory of Biochemistry and Molecular Biology, CNR FRE, Faculty of Medicine IFR Biomolecules, University of Reims Champagne-Ardenne, France.
Monboisse
Jean-Claude
JC
Gorisse
Marie-Claude
MC
Gillery
Philippe
P
D000375:Aging / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001798:Blood Proteins / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019394:Ki-67 Antigen / Q000187:drug effects / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*
D001798:Blood Proteins; D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; D011506:Proteins; D008315:Malondialdehyde; D003094:Collagen; D020169:Caspases