title: Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats.
abstract: OBJECTIVE
  Hypertension is associated with increased levels of circulating cytokines and recent studies have shown that innate immunity contributes to hypertension. The mechanisms which hypertension stimulates immune response remain unclear, but may involve formation of neo-antigens that activate the immune system. Toll like receptor 4 (TLR4) is an innate immune receptor that binds a wide spectrum of exogenous (lipopolysaccharide) and endogenous ligands. TLR4 signaling leads to activation of nuclear factor kappa B (NFκB) and transcription of genes involved in inflammatory response. We previously demonstrated that TLR4 blockade reduces blood pressure and the augmented vascular contractility in spontaneously hypertensive rats (SHR). Here we hypothesized that inhibition of TLR4 ameliorates the vascular inflammatory process by a NFκB signaling pathway.
  
  
  METHODS
  SHR and Wistar rats were treated with anti-TLR4 antibody (1μg/day) or unspecific IgG for 15days (i.p.).
  
  
  RESULTS
  Anti-TLR4 treatment decreased production of reactive oxygen species and expression of IL-6 cytokine in mesenteric resistance arteries from SHR, when compared with IgG-treated SHR. Anti-TLR4 treatment also abolished the increased vascular reactivity to noradrenaline observed in IgG-treated SHR, as described before, and inhibition of NFκB decreased noradrenaline responses only in IgG-treated SHR. Mesenteric arteries from SHR treated with anti-TLR4 displayed decreased expression of MyD88, but not TRIF, key molecules in TLR4 signaling. Phosphorylation of p38 and NF-κB p65 were decreased in arteries from anti-TLR4-treated SHR versus IgG-treated SHR.
  
  
  CONCLUSIONS
  Together, these results suggest that TLR4 is a key player in hypertension and vascular inflammatory process by a NFκB signaling pathway.
authors.affiliation: Institute of Health Sciences, Federal University of Mato Grosso, Av. Alexandre Ferronato, 1200, Reserva 35, Setor Industrial, Sinop, MT 78550-000, Brazil; Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: gifacholi@yahoo.com.br.
authors.forename: G F
authors.initials: GF
authors.lastname: Bomfim
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: cinthya.echem@gmail.com.
authors.forename: C
authors.initials: C
authors.lastname: Echem
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: cla_cbm@hotmail.com.
authors.forename: C B
authors.initials: CB
authors.lastname: Martins
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: tiago.januario@uol.com.br.
authors.forename: T J
authors.initials: TJ
authors.lastname: Costa
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: simone.sartoretto@gmail.com.
authors.forename: S M
authors.initials: SM
authors.lastname: Sartoretto
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: reichlerusp@gmail.com.
authors.forename: R A
authors.initials: RA
authors.lastname: Dos Santos
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: cidora@yahoo.com.
authors.forename: M A
authors.initials: MA
authors.lastname: Oliveira
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: eliakamine@gmail.com.
authors.forename: E H
authors.initials: EH
authors.lastname: Akamine
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: zbfortes@icb.usp.br.
authors.forename: Z B
authors.initials: ZB
authors.lastname: Fortes
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Avenida Bandeirantes 3900, Ribeirao Preto, Sao Paulo 14049-900, Brazil. Electronic address: rtostes@usp.br.
authors.forename: R C
authors.initials: RC
authors.lastname: Tostes
authors.affiliation: Department of Physiology, Georgia Regents University, 1120 15th St, Augusta, GA 30912, United States of America. Electronic address: cwebb@gru.edu.
authors.forename: R C
authors.initials: RC
authors.lastname: Webb
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor LineuPrestes, 1524, Sala 205, São Paulo, SP 05508-900, Brazil. Electronic address: mhcarval@icb.usp.br.
authors.forename: M H C
authors.initials: MH
authors.lastname: Carvalho
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006973:Hypertension / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D017382:Reactive Oxygen Species; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4
keywords: Hypertension; Innate immune response; NF-κB; Toll-like receptor