Pitavastatin up-regulates the induction of iNOS through enhanced stabilization of its mRNA in pro-inflammatory cytokine-stimulated hepatocytes.
Studies have indicated that protective effects of statins (HMG-CoA reductase inhibitor) are associated with the regulation of endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS) in heart and liver diseases. Statins have been reported to enhance hepatic NO production and decrease the vascular tone in patients with cirrhosis. However, it is unclear which NOS contributes to the increased NO production. We hypothesized that statins are involved in the up-regulation of iNOS in inflammatory liver, resulting in decreased hepatic resistance. Primary cultured rat hepatocytes were treated with pro-inflammatory cytokine interleukin (IL)-1beta in the presence or absence of pitavastatin. Pretreatment of cells with pitavastatin resulted in up-regulation of iNOS induction by IL-1beta, followed by increased NO production. Pitavastatin had no effects on the degradation of IkappaB or activation of NF-kappaB. However, pitavastatin super-induced the up-regulation of type I IL-1 receptor (IL-1RI), which is essential for iNOS induction in addition to the IkappaB/NF-kappaB pathway. Mevalonate and geranylgeranylpyrophosphate blocked the stimulatory effects of pitavastatin on iNOS and IL-1RI induction. Transfection experiments revealed that pitavastatin increased the stability of iNOS mRNA rather than its promoter transactivation. In support of this observation, pitavastatin increased the antisense-transcript corresponding to the 3'-UTR of iNOS mRNA, which stabilizes iNOS mRNA by interacting with the 3'-UTR- and RNA-binding proteins. These findings demonstrate that pitavastatin up-regulates iNOS by the stabilization of its mRNA, presumably through the super-induction of IL-1RI and antisense-transcript. This implies that statins may contribute to a novel potentiated treatment in liver injuries including cirrhosis.
Habara
Kozo
K
Department of Surgery, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan.
Hamada
Yoshinori
Y
Yamada
Masanori
M
Tokuhara
Katsuji
K
Tanaka
Hironori
H
Kaibori
Masaki
M
Kamiyama
Yasuo
Y
Nishizawa
Mikio
M
Ito
Seiji
S
Okumura
Tadayoshi
T
D000818:Animals; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects* / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011804:Quinolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053573:Receptors, Interleukin-1 Type I / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D053583:Interleukin-1beta; D011106:Polyisoprenyl Phosphates; D011804:Quinolines; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins; D052247:Nitric Oxide Synthase Type II; C108475:pitavastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid