Lipid-independent effects of an estrogen-statin combination: inhibition of expression of adhesion molecules and plasminogen activator inhibitor--I in human endothelial cell cultures.
OBJECTIVE
Estrogens have been shown to elicit beneficial effects on the cardiovascular system by modulating the lipid profile as well as by direct vascular actions. Since estrogenic cardioprotection has still been not confirmed by randomized interventional trials, the combination with statins, which have been proved to act in a cardioprotective fashion, is of special interest. Statins are lipid-lowering drugs, but direct vascular effects also seem to be of importance in this case. Apart from some clinical studies investigating the effect of such combination therapy on the lipid profile, no reports of a possible influence on biochemical markers of vascular function are yet available. The aim of the present study was to investigate, for the first time, lipid-independent effects of an estrogen-statin combination on markers of vascular endothelial function.


METHODS
Experiments were conducted using endothelial cell cultures from human umbilical veins. Markers of endothelial function chosen were adhesion molecules, which are involved in the early stages of atherosclerosis, and plasminogen activator inhibitor-1 (PAI-1), which is an independent risk factor for the development of cardiovascular disease. The concentrations of soluble forms of the adhesion molecules E-selectin and intercellular adhesion molecule (ICAM) as well as concentrations of PAI-1 were measured after the addition of 17 beta-estradiol, fluvastatin and equimolar combinations of the two in concentrations of 0.01, 0.1 and 1 mumol/l.


RESULTS
Both drugs significantly reduced concentrations of E-selectin and ICAM, and the effect of the combination was not superior to that of the monosubstances. In addition, both substances were able to inhibit the synthesis of PAI-1. In this case the effect of the combination was significantly greater than that of the monosubstances.


CONCLUSIONS
In summary, an estrogen-statin therapy is able to elicit lipid-independent positive modulations on the expression of cell adhesion molecules and the synthesis of PAI-1. The estrogen-statin combination showed partially additive effects and no negative, antagonistic actions. Since the combination of statins with hormone replacement therapy may attain clinical significance in preventing cardiovascular disease, it seems worthwhile to elucidate further the direct vascular effects of this combination therapy, especially in postmenopausal women with pre-existing coronary disease.
Seeger
H
H
Endocrinology and Menopause Section, Department of Obstetrics and Gynecology, University of Tuebingen, Schleichstrasse 4, 72 076 Tuebingen, Germany.
Wallwiener
D
D
Mueck
A O
AO
D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*
D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; D018799:Intercellular Adhesion Molecule-1; D000077340:Fluvastatin; D004958:Estradiol