Effect of an estrogen/statin combination on biochemical markers of endothelial function in human coronary artery cell cultures.
OBJECTIVE
The combination of an estrogen with a statin for therapy of postmenopausal women is of interest because both substance classes exert beneficial effects on the lipid profile. However, both substance classes also elicit positive direct effects on the vasculature. Therefore in the present in vitro study an estrogen/statin combination was investigated for its effect on biochemical markers of endothelial function.


METHODS
In endothelial cell cultures from human coronary arteries, the effect of estradiol/fluvastatin, alone and in equimolar combinations, were tested at the concentrations 0.01, 0.1, and 1 microM. The vasodilator prostacyclin, the vasoconstrictor endothelin, endothelial nitric oxide synthase (responsible for synthesis of the vasodilator nitric oxide), the procoagulatory factor plasminogen activator inhibitor-1, and the monocyte chemoattractant protein were chosen as markers.


RESULTS
The estradiol/fluvastatin combination was able to increase prostacyclin production (25-100%) in an additive manner. The reduction of endothelin synthesis in the range of 21-46% was higher with the combination than with the monosubstances; the reduction, however, was not statistically significant. The expression of endothelial nitric oxide synthase was not significantly increased by the combination compared with the monosubstances, however, a tendency to an additive increase was observed. For the synthesis of plasminogen activator inhibitor-1, no significant changes were seen for either the monosubstances or the combination. The synthesis of monocyte chemoattractant protein-1 was decreased by the combination between 21% and 40%; the decrease, however, was not statistically significant compared with the effect of the monosubstances. The effective estradiol concentrations are higher than can be achieved by replacement therapy; in contrast, fluvastatin was effective at concentrations that can be reached during clinical treatment.


CONCLUSIONS
These results indicate that an estrogen/statin combination exerts beneficial effects on the vasculature that seem to be superior to the effects of the monosubstances. The changes found for the biochemical markers can improve endothelial function. The presented results should encourage the performance of clinical studies in cardiovascular risk patients with estrogen/statin combinations.
Mueck
A O
AO
Department of Obstetrics and Gynecology, University of Tuebingen, Germany.
Seeger
H
H
Deuringer
F U
FU
Wallwiener
D
D
D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers; D002318:Cardiovascular Diseases / Q000517:prevention & control; D002460:Cell Line / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D011464:Epoprostenol / 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*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D017698:Postmenopause
D000924:Anticholesteremic Agents; D015415:Biomarkers; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; D004958:Estradiol; D011464:Epoprostenol; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III