Matrix-degrading and pro-inflammatory changes in human vascular endothelial cells exposed to cigarette smoke condensate

Cigarette smoking has been associated with an increase in the severity and prevalence of atherosclerosis in the abdominal aorta. To begin our investigation of this finding, we used an integrated approach combining gene expression profiling, protein analysis, cytokine measurements, and cytotoxicity d...

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Bibliographic Details
Published in:Cardiovascular toxicology 2003, Vol.3 (2), p.101-118
Main Authors: Nordskog, Brian K, Blixt, Allison D, Morgan, Walter T, Fields, Wanda R, Hellmann, Gary M
Format: Article
Language:English
Subjects:
Adult
Aorta, Abdominal - cytology
Cell cycle
Cell Line
Coronary Artery Disease - etiology
Coronary Artery Disease - metabolism
Coronary Vessels - cytology
Culture Media, Conditioned - metabolism
Cytokines - metabolism
Dose-Response Relationship, Drug
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
Gene expression
Gene Expression - drug effects
Gene Expression Profiling
Heme Oxygenase (Decyclizing) - genetics
Heme Oxygenase (Decyclizing) - metabolism
Heme Oxygenase-1
Humans
Integrated approach
Male
Matrix Metalloproteinases - genetics
Matrix Metalloproteinases - metabolism
Membrane Proteins
Middle Aged
Nicotiana
Nicotine - toxicity
Proteins
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - biosynthesis
Smoke - adverse effects
Up-Regulation
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Summary:Cigarette smoking has been associated with an increase in the severity and prevalence of atherosclerosis in the abdominal aorta. To begin our investigation of this finding, we used an integrated approach combining gene expression profiling, protein analysis, cytokine measurements, and cytotoxicity determinations to examine molecular responses of cultured human aortic and coronary endothelial cells exposed to cigarette smoke condensate (CSC) and nicotine. Exposure of endothelial cells to CSC (30 and 60 microg/mL TPM) for 24 h resulted in minimal cytotoxicity, and the upregulation of genes involved in matrix degradation (MMP-1, MMP-8, and MMP-9), xenobiotic metabolism (HO-1 and CYP1A2), and downregulation of genes involved in cell cycle regulation (including TOP2A, CCNB1, CCNA, CDKN3). Exposure of cells to a high physiological concentration of nicotine resulted in few differentially expressed genes. Immunoblot analysis of proteins selected from genes shown to be differentially regulated by microarray analysis revealed similar responses. Finally, a number of inflammatory cytokines measured in culture media were elevated in response to CSC. Together, these results describe a complex proinflammatory response, possibly mediating the recruitment of leukocytes through cytokine signaling. Additionally, fibrous cap destabilization may be facilitated by matrix metalloproteinase upregulation.
ISSN:1530-7905
1559-0259
1530-7905
DOI:10.1385/ct:3:2:101