Endothelial cell fibrinolysis: Transcriptional regulation of fibrinolytic protein gene expression (t-PA, n-PA, and PAI-1) by low alcohol

Epidemiological studies have associated moderate alcohol consumption with a reduced risk for coronary artery disease (CAD) and myocardial infarction ( MI). This cardioprotection may be attributed to alcohol-induced changes in a variety of cellular functions, including increased fibrinolysis. Fibrinol ysis is important in regulating normal hemostasis. Endothelial cells (ECs) synthesize fibrinolytic proteins, t-PA, u-PA, and PAs inhibitor, PAI-1. Sys temic factors, i.e., alcohol, that affect one or more of these components, resulting in increased EC fibrinolysis, will reduce the risk for thrombosis , CAD, and MI and afford cardioprotection. These studies will identify/defi ne the effects of low ethanol (<0.1%, v/v) on the expression of PAs, PAI-1, and surface-localized fibrinolytic activity in cultured ECs. Low ethanol e xerted a short-term time- and dose-dependent increase (similar to 5- to 8-f old) in activity at similar to 20 min and 0.05% ethanol, which was sustaine d for similar to 1 hr. On the other hand, a single brief exposure to low et hanol (<0.1%, <120 min), followed by 4-24 hr incubation in the absence of e thanol, showed a time- and dose-dependent increase (similar to 2- to 3-fold ) in PAs antigen/mRNA and a concomitant similar to 2- to 3-fold sustained i ncrease (similar to 24 hr) in fibrinolytic activity. Further nuclear transc ription run-on assays and transient transfection experiments, using pPAs/lu c and pPAI-1/luc promoter constructs, demonstrated that low ethanol transcr iptionally upregulates t-PA and u-PA gene expression and downregulates PAI- 1 gene expression. These combined studies have described a feasible molecul ar mechanism by which low ethanol can induce and sustain increased surface- localized EC fibrinolysis that may underlie and contribute, in part, to the cardioprotective benefit associated with moderate alcohol consumption.