Toxicogenomic Analysis of Mainstream Tobacco Smoke-Exposed Mice Reveals Repression of Plasminogen Activator Inhibitor-1 Gene in Heart
Source: Inhalation Toxicology, Volume 21, Number 1, January 2009 , pp. 78-85(8)
Publisher: Informa Healthcare
Abstract:Tobacco smoking is associated with cardiovascular pathology. However, the molecular mechanisms of tobacco smoke exposure that lead to initiation or exacerbation of cardiovascular disease are unclear. In this study, the effects of mainstream tobacco smoke (MTS) on global transcription in the heart were investigated. Male C57B1/CBA mice were exposed to MTS from 2 cigarettes daily, 5 days/wk for 6 or 12 wk. Mice were sacrificed immediately, or 6 wk following the last cigarette. High-density DNA microarrays were used to characterize global gene expression changes in whole heart. Fifteen genes were significantly differentially expressed following exposure to MTS. Among these genes, cytochrome P-450 1A1 (Cyp1A1) was upregulated by 12-fold, and Serpine-1 (plasminogen activator inhibitor-1, PAI-1) was downregulated by 1.7-fold. Concomitant increase in Cyp1A1 protein levels and decrease in total and active PAI-1 protein was observed in tissue extracts by Western blot assay and enzyme-linked immunosorbent assay (ELISA), respectively. Observed changes were transient and were partially reversed during break periods. Thus, gene expression profiling of heart tissue revealed a novel cardiovascular mechanism operating in response to MTS. Our results suggest a potential role for PAI-1 in MTS-induced cardiovascular pathology.
Document Type: Research Article
Affiliations: 1: Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario 2: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario 3: Biostatistics and Epidemiology Division, Health Canada, Ottawa, Ontario, Canada
Publication date: January 1, 2009