P260	Atorvastatin prevents hypoxia-induced inhibition of endothelial nitric oxide synthase expression but does not affect heme oxygenase-1 in human microvascular endothelial cells.
1J.Dulak, 1A.Loboda, 1A.Jazwa, 2J.Balla, 3G.Molema, 1A.Jozkowicz
1Faculty of Biotechnology, Jagiellonian University, Kraków, PL; 2Clinic of Nephrology, University of Debrecen, Debrecen, HU; 3Department of Pathology and Laboratory Medicine, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, NL.

Background: Beneficial cardiovascular effects of statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are particularly assigned to the modulation of inflammation. Endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) are listed among the crucial protective, anti-inflammatory and pro-angiogenic genes in the vasculature. Hypoxia was demonstrated to decrease eNOS expression in macrovascular endothelial cells, but the data on the effect of hypoxia on eNOS and HO-1 in microvascular endothelial cells and modulation by statins are lacking. Methods and results: Hypoxia (1% O2, 6-24 hours) down-regulated eNOS expression, as shown by real-time RT-PCR and ELISA. In contrast, expression of HO-1 did not change significantly, although hemin, a substrate and inducer of HO-1 potently upregulated HO-1 protein level, indicating that no effect of atorvastatin on HO-1 did no reflect the poor responsiveness of the cells. Atorvastatin at pharmacologically relevant concentrations (0.1 - 1 μM) moderately enhanced the expression of eNOS in normoxia and, importantly, it completely prevented its hypoxia-induced decay. However, in the same cells atorvastatin was ineffective in modulation of neither HO-1 protein level nor enzyme activity. Also longer (48-72 hours) incubation with 1-10 μM concentrations of the drug was not effective in modulation of HO-1. Conclusions: Atorvastatin at pharmacological concentrations prevents attenuation of eNOS expression in hypoxia. However, our data suggest that statins at pharmacologically relevant doses may not affect HO-1 expression. Supported by grant PBZ-KBN 107/P04/2004

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.