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.
Highlights
Tobacco smoking is associated with cardiovascular pathology
Our findings reveal the repression of plasminogen activator inhibitor 1 (PAI-1), a key gene involved in fibrinolysis, in the hearts of mice exposed to mainstream tobacco smoke (MTS)
Global analysis of gene expression in the hearts of mice exposed to MTS revealed surprisingly few genes exhibiting differential expression
Summary
Tobacco smoking is associated with cardiovascular pathology. the molecular mechanisms of tobacco smoke exposure that lead to initiation or exacerbation of cardiovascular disease are unclear. We used Agilent high-density DNA microrrays to examine global transcriptional changes in heart tissue of mice exposed to mainstream tobacco smoke (MTS) for 6 or 12 wk, respectively. Our findings reveal the repression of plasminogen activator inhibitor 1 (PAI-1), a key gene involved in fibrinolysis, in the hearts of mice exposed to MTS. This finding is in contrast to established evidence demonstrating an increase in plasma PAI-1 activity and impaired fibrinolysis in cardiovascular diseases (Gils & Declerck, 2004; Hamsten et al, 1987; Juhan-Vague et al, 1987; Vaughan, 2005). We suggest a potential nonfibrinolytic role for PAI-1 following prolonged exposure to MTS
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