title: Opposing roles of nitric oxide and rho-kinase in lipid metabolism in mice.
abstract: Dyslipidemia is a life-style disorder and is one of the important risk factors of cardiovascular diseases. Nitric oxide (NO) exerts beneficial effects on lipid metabolism through activation of hepatic sterol regulatory element-binding protein (SREBP)-2, a transcriptional factor for cholesterol metabolism and expression of LDL receptor, while Rho-kinase, an effecter protein of small G protein, RhoA, contributes to the pathogenesis of metabolic syndrome through suppressing the whole body energy consumption. However, the crosstalk between NO and Rho-kinase in regulation of lipid metabolism remains to be elucidated. In the present study, we used male wild-type (WT) mice and mice lacking three isoforms of NO synthase (NOSs(-/-)). WT mice were fed either normal diet (ND) or high-fat diet (HFD), while NOSs(-/-) mice were fed ND with or without a selective Rho-kinase inhibitor, fasudil (100 mg/kg/day), for 6 weeks. At 6 weeks, plasma NOx concentration was significantly decreased and Rho-kinase activity and lipid levels were significantly elevated in HFD-fed WT mice and NOSs(-/-) mice compared with ND-fed WT mice. In the liver, SREBP-2 activity was reduced in NOSs(-/-) mice. Fasudil ameliorated lipid levels in HFD-fed WT mice and NOSs(-/-) mice without affecting SREBP-2 activity or LDL receptor expression, whereas it significantly enhanced phosphorylation of AMP-activated kinase (AMPK) in the liver and skeletal muscle. Importantly, the beneficial metabolic effects of fasudil were absent in HFD-fed AMPK(-/-) mice. These results provide the first evidence that NO and Rho-kinase play opposing roles for the lipid metabolism, suggesting that Rho-kinase inhibitors could be novel therapeutic agents of dyslipidemia.
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Noda
authors.forename: Shigeo
authors.initials: S
authors.lastname: Godo
authors.forename: Hiroki
authors.initials: H
authors.lastname: Saito
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000818:Animals; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D054460:rho-Associated Kinases / Q000378:metabolism / Q000502:physiology*
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D009569:Nitric Oxide; D002784:Cholesterol; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; D055372:AMP-Activated Protein Kinases