title: Simvastatin induces a central hypotensive effect via Ras-mediated signalling to cause eNOS up-regulation.
abstract: OBJECTIVE
  Clinical studies indicate that statins have a BP-lowering effect in hypercholesterolemic individuals with hypertension. Specifically, statins modulate BP through the up-regulation of endothelial NOS (eNOS) activation in the brain. However, the signalling mechanisms through which statins enhance eNOS activation remain unclear. Therefore, we examined the possible signalling pathways involved in statin-mediated BP regulation in the nucleus tractus solitarii (NTS).
  
  
  METHODS
  To investigate the involvement of Ras and other signalling pathways in simvastatin-induced effects on BP, BP and renal sympathetic nerve activity (RSNA) were determined in spontaneously hypertensive rats (SHRs) before and after i.c.v. administration of simvastatin in the absence and presence of a Ras-specific inhibitor (farnesyl thiosalicylic acid, FTS), a geranylgeranyltransferase inhibitor (GGTI-2133), a PI3K inhibitor (LY294002) or a MAPK-ERK kinase (MEK) inhibitor (PD98059).
  
  
  RESULTS
  FTS significantly attenuated the decrease in BP and increased NO evoked by simvastatin and reversed the decrease in basal RSNA induced by simvastatin. Immunoblotting and pharmacological studies showed that inhibition of Ras activity by FTS significantly abolished simvastatin-induced phosphorylation of ERK1/2, ribosomal protein S6 kinase (RSK), Akt and decreased eNOS phosphorylation. Likewise, administration of Akt and ERK1/2 signalling inhibitors, LY294002 and PD98059, attenuated the reduction in BP evoked by simvastatin. Furthermore, i.c.v. simvastatin decreased Rac1 activation and the number of ROS-positive cells in the NTS.
  
  
  CONCLUSIONS
  Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras-mediated activation of the PI3K-Akt and ERK1/2-RSK signalling pathways, which then up-regulates eNOS activation.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Cheng
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Ho
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Chang
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Cheng
authors.forename: Tung-Chen
authors.initials: TC
authors.lastname: Yeh
authors.forename: Ling-Zong
authors.initials: LZ
authors.lastname: Hong
authors.forename: Gwo-Ching
authors.initials: GC
authors.lastname: Sun
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Ching-Jiunn
authors.initials: CJ
authors.lastname: Tseng
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007668:Kidney / Q000294:innervation; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D017552:Solitary Nucleus / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D013997:Time Factors; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins
keywords: Ras; hypertension; isoprenylation; nitric oxide; nucleus tractus solitarii; statins
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