Peroxisome proliferator-activated receptor alpha agonists increase nitric oxide synthase expression in vascular endothelial cells.
OBJECTIVE
There has been accumulating evidence demonstrating that activators for peroxisome proliferator-activated receptor alpha (PPARalpha) have antiinflammatory, antiatherogenic, and vasodilatory effects. We hypothesized that PPARalpha activators can modulate endothelial nitric oxide synthase (eNOS) expression and its activity in cultured vascular endothelial cells.


RESULTS
Bovine aortic endothelial cells were treated with the PPARalpha activator fenofibrate. The amount of eNOS activity and the expression of eNOS protein and its mRNA were determined. Our data show that treatment with fenofibrate for 48 hours resulted in an increase in eNOS activity. Fenofibrate failed to increase eNOS activity within 1 hour. Fenofibrate also increased eNOS protein as well as its mRNA levels. RU486, which has been shown to antagonize PPARalpha action, inhibited the fenofibrate-induced upregulation of eNOS protein expression. WY14643 and bezafibrate also increased eNOS protein levels, whereas rosiglitazone did not. Transient transfection experiments using human eNOS promoter construct showed that fenofibrate failed to enhance eNOS promoter activity. Actinomycin D studies demonstrated that the half-life of eNOS mRNA increased with fenofibrate treatment.


CONCLUSIONS
PPARalpha activators upregulate eNOS expression, mainly through mechanisms of stabilizing eNOS mRNA. This is a new observation to explain one of the mechanisms of PPARalpha-mediated cardiovascular protection.
Goya
Kayoko
K
Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Sumitani
Satoru
S
Xu
Xin
X
Kitamura
Tetsuhiro
T
Yamamoto
Hiroyasu
H
Kurebayashi
Shogo
S
Saito
Hiroshi
H
Kouhara
Haruhiko
H
Kasayama
Soji
S
Kawase
Ichiro
I
D000818:Animals; D001011:Aorta; D001629:Bezafibrate / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D003609:Dactinomycin / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006207:Half-Life; D015735:Mifepristone / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D003609:Dactinomycin; D009569:Nitric Oxide; D015735:Mifepristone; C006253:pirinixic acid; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D011345:Fenofibrate; D001629:Bezafibrate