Increase in the transcriptional activity of the endothelial nitric oxide synthase gene with fluvastatin: a relation with the -786T>C polymorphism.
HMG-CoA reductase inhibitors (statins) increase endothelial nitric oxide (NO) production, although the precise mechanism of this statin induced increase in NO production remains to be elucidated. We examined endothelial nitric oxide synthase (eNOS) mRNA levels, mRNA stability and the transcriptional activities of the eNOS gene in human umbilical vein endothelial cells treated with fluvastatin and simvastatin. We further examined whether the effects of these statins differ dependent upon the -786T>C polymorphism in the eNOS gene, and whether these statins affect gene expression of replication protein A1 (RPA1), which is known to reduce the transcriptional activity of the eNOS gene with the -786C allele. Utilizing the real-time reverse transcription-polymerase chain reaction, fluvastatin significantly increased eNOS mRNA levels and mRNA stability, and decreased RPA1 mRNA levels. Luciferase reporter gene assays revealed that fluvastatin significantly increased the transcriptional activity of the eNOS gene. The effect of fluvastatin was stronger in the -786C/C genotype than in the -786T/T genotype. Simvastatin increased eNOS mRNA levels and mRNA stability, but did not affect the transcriptional activity of the eNOS gene. Fluvastatin increased eNOS mRNA levels by enhancing both the transcriptional activity and mRNA stability. The effect of fluvastatin on the transcriptional activity was augmented in the -786C/C genotype, probably because of a decrease in RPA1 gene expression. Simvastatin increased eNOS mRNA levels only by enhancing mRNA stability. The present study suggests that fluvastatin increases endothelial NO activity and thus may be more beneficial to patients with the -786C allele.
Abe
Koji
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Nakayama
Masafumi
M
Yoshimura
Michihiro
M
Nakamura
Shota
S
Ito
Teruhiko
T
Yamamuro
Megumi
M
Sakamoto
Tomohiro
T
Miyamoto
Yoshihiro
Y
Yoshimasa
Yasunao
Y
Saito
Yoshihiko
Y
Nakao
Kazuwa
K
Yasue
Hirofumi
H
Ogawa
Hisao
H
D002460:Cell Line; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D015533:Transcriptional Activation
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D012333:RNA, Messenger; D000077340:Fluvastatin; D019821:Simvastatin