title: Atherogenic properties of human monocytes induced by the carboxyl terminal proteolytic fragment of alpha-1-antitrypsin.
abstract: Atherosclerotic plaques contain a significant number of macrophage foam cells and are associated with an inflammatory state. Inflammation induces the secretion from monocytes and other cells of cytokines, reactive oxygen species, proteinases and proteinase inhibitors among many other molecular species. AAT is prominent among the serine proteinase inhibitors and is an important regulator of leukocyte elastase and proteinase-3. It has been shown that the stable AAT-proteinase complex can upregulate AAT biosynthesis, and we have shown that the shorter, carboxyl terminal peptide (C-36) resulting from proteinase cleavage of AAT polymerizes, and in its fibrillar form alters cellular metabolism. To test for a possible link between the inflammation-generated C-36 peptide and cellular processes associated with atherogenesis, we have studied the effects of the fibrillar form of this peptide at varying concentrations on human monocytes in culture. We have found that fibrillar C-36 at concentrations of greater than or equal to 5 micromol/l in monocyte cultures for 24 h significantly increases LDL binding and uptake, upregulates LDL receptors, induces cytokine production and glutathione reductase activity, and upregulates AAT synthesis. The expression of CD36 protein, LDL Scavenger receptor, is also upregulated by fibrillar C-36 and native LDL in the presence of C-36-activated monocytes is more oxidized than with unactivated control monocytes. The majority of monocytes cultured for 24 h in the presence of C-36 fibrils were transformed morphologically into macrophages. These data establish a direct molecular link, mediated by C-36 peptide of AAT, between inflammation and the oxidation and accumulation of lipid in monocyte-derived macrophages. This may be important for an understanding of the events conducive to atherogenesis.
authors.affiliation: Gastroenterology-Hepatology Division, Department of Medicine, Wallenberg Laboratory, University Hospital Malmö, S-20502, Malmö, Sweden. sabina.janciauskiene@medforsk.mas.lu.se
authors.forename: S
authors.initials: S
authors.lastname: Janciauskiene
authors.forename: H T
authors.initials: HT
authors.lastname: Wright
authors.forename: S
authors.initials: S
authors.lastname: Lindgren
mesh_terms: D000704:Analysis of Variance; D017209:Apoptosis; D001161:Arteriosclerosis / Q000503:physiopathology*; D018955:CD36 Antigens / Q000032:analysis; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D005980:Glutathione Reductase / Q000096:biosynthesis*; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000502:physiology; D008262:Macrophage Activation; D009000:Monocytes / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000515:alpha 1-Antitrypsin / Q000096:biosynthesis*
chemical_list: D018955:CD36 Antigens; D016207:Cytokines; D008077:Lipoproteins, LDL; D010446:Peptide Fragments; D012333:RNA, Messenger; D011973:Receptors, LDL; D000515:alpha 1-Antitrypsin; D005980:Glutathione Reductase