Document Detail


Atherogenic properties of human monocytes induced by the carboxyl terminal proteolytic fragment of alpha-1-antitrypsin.
MedLine Citation:
PMID:  10559512     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
S Janciauskiene; H T Wright; S Lindgren
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Atherosclerosis     Volume:  147     ISSN:  0021-9150     ISO Abbreviation:  Atherosclerosis     Publication Date:  1999 Dec 
Date Detail:
Created Date:  2000-01-06     Completed Date:  2000-01-06     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0242543     Medline TA:  Atherosclerosis     Country:  IRELAND    
Other Details:
Languages:  eng     Pagination:  263-75     Citation Subset:  IM    
Affiliation:
Gastroenterology-Hepatology Division, Department of Medicine, Wallenberg Laboratory, University Hospital Malmö, S-20502, Malmö, Sweden. sabina.janciauskiene@medforsk.mas.lu.se
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MeSH Terms
Descriptor/Qualifier:
Analysis of Variance
Antigens, CD36 / analysis
Apoptosis
Arteriosclerosis / physiopathology*
Cells, Cultured
Cytokines / biosynthesis,  metabolism*
Glutathione Reductase / biosynthesis*
Humans
Lipid Peroxidation / physiology
Lipoproteins, LDL / metabolism*,  physiology
Macrophage Activation
Monocytes / metabolism*
Peptide Fragments / metabolism,  physiology
RNA, Messenger / analysis
Receptors, LDL / genetics
Reverse Transcriptase Polymerase Chain Reaction
alpha 1-Antitrypsin / biosynthesis*
Chemical
Reg. No./Substance:
0/Antigens, CD36; 0/Cytokines; 0/Lipoproteins, LDL; 0/Peptide Fragments; 0/RNA, Messenger; 0/Receptors, LDL; 0/alpha 1-Antitrypsin; EC 1.8.1.7/Glutathione Reductase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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