Abstract
The mechanism by which moderate alcohol ingestion lowers the risk of cardiovascular disease is unknown but may be due, in part, to the ability of alcohol to increase the level of tissue-type plasminogen activator (t-PA). Human endothelial cells were treated with low concentrations of ethanol (0.25-25 mM, 0-24 h), which are associated with moderate alcohol consumption. Although treatment with ethanol alone did not affect t-PA gene transcription or mRNA expression, it augmented isoproterenol (ISO)-stimulated t-PA gene transcription and mRNA levels by 3.4- and 2.8-fold, respectively, and decreased plasminogen activator inhibitor-1 mRNA levels by 65%. These effects of ethanol correlated with 2.5- and 6.9-fold increases in ISO-stimulated cyclic AMP levels and 4x-cyclic AMP response element heterologous promoter activity, respectively. To determine whether alcohol-induced changes in agonist-stimulated cyclic AMP levels were because of modulation of guanine nucleotide-binding proteins (G proteins), we assessed the effects of ethanol on Galphas and Galphai2. Although ethanol did not affect the expression of Galphas or Galphai2, it increased ISO-stimulated Galphas GTPase and GTP binding activity by 2.2- and 2.9-fold and decreased UK14304-stimulated Galphai2 GTPase and GTP binding activity by 38 and 80%. These results indicate that treatment with relatively low concentrations of ethanol enhances agonist-stimulated cyclic AMP-dependent t-PA gene transcription in vascular endothelial cells through differential modulation of G protein.
Highlights
Lytic enzyme, tissue-type plasminogen activator (t-PA),1 and its inhibitor, plasminogen activator inhibitor (PAI)-1 are important in regulating the thrombotic process [5]
Similar results were observed with human aortic endothelial cells. These results indicate that low concentrations of ethanol (Ͻ 10 mM) augment isoproterenolstimulated t-PA expression in vascular endothelial cells
Effect of Ethanol on G-protein Expression—Because isoproterenol stimulated an increase in t-PA gene transcription and mRNA expression is dependent upon coupling to specific Gproteins, G␣s, we investigated whether low concentrations of alcohol affect G-protein expression
Summary
Lytic enzyme, tissue-type plasminogen activator (t-PA), and its inhibitor, plasminogen activator inhibitor (PAI)-1 are important in regulating the thrombotic process [5]. Higher concentrations of alcohol (i.e. Ͼ100 mM) have been shown to modulate guanine nucleotide-binding protein (G-protein) activity and cAMP levels in neuronal tissues or cell lines [17,18,19], it is not known whether lower concentrations of alcohol (i.e. Ͻ5 mM) have similar effects in vascular endothelial cells and whether these effects, if present, translate into specific gene expression that contributes to the cardiovascular protective effects of moderate alcohol ingestion. The purpose of this study is to characterize the effects of alcohol on G-protein function in vascular endothelial cells and to determine whether concentrations of alcohol that are associated with the ingestion of less than two alcoholic beverages can up-regulate t-PA expression via G-protein-mediated cAMP-dependent signaling pathways. Because the rupture of atherosclerotic plaques with ensuing thrombosis is widely believed to be the predominant etiology underlying acute coronary syndromes [4], endogenous mediators such as the proteo-
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