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J Biol Chem, Vol. 274, Issue 17, 12055-12060, April 23, 1999

Activation of Guanine Nucleotide-binding Proteins and Induction of Endothelial Tissue-type Plasminogen Activator Gene Transcription by Alcohol

Atsushi Miyamoto, Shui-Xiang Yang^§, Ulrich Laufs^§, Xiu-Lu Ruan^§, and James K. Liao^§

From the ^§ Cardiovascular Division, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115 and the  Department of Veterinary Pharmacology, Kagoshima University, Kagoshima 890-0065, Japan

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 4×-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 G_s and G_i2. Although ethanol did not affect the expression of G_s or G_i2, it increased ISO-stimulated G_s GTPase and GTP binding activity by 2.2- and 2.9-fold and decreased UK14304-stimulated G_i2 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.

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