title: Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats.
abstract: Activation of TLRs (Toll-like receptors) induces gene expression of proteins involved in the immune system response. TLR4 has been implicated in the development and progression of CVDs (cardio-vascular diseases). Innate and adaptive immunity contribute to hypertension-associated end-organ damage, although the mechanism by which this occurs remains unclear. In the present study, we hypothesize that inhibition of TLR4 decreases BP (blood pressure) and improves vascular contractility in resistance arteries from SHR (spontaneously hypertensive rats). TLR4 protein expression in mesenteric resistance arteries was higher in 15-week-old SHR than in age-matched Wistar controls or in 5-week-old SHR. To decrease the activation of TLR4, 15-week-old SHR and Wistar rats were treated with anti-TLR4 (anti-TLR4 antibody) or non-specific IgG control antibody for 15 days (1 μg per day, intraperitoneal). Treatment with anti-TLR4 decreased MAP (mean arterial pressure) as well as TLR4 protein expression in mesenteric resistance arteries and IL-6 (interleukin 6) serum levels from SHR when compared with SHR treated with IgG. No changes in these parameters were found in treated Wistar control rats. Mesenteric resistance arteries from anti-TLR4-treated SHR exhibited decreased maximal contractile response to NA (noradrenaline) compared with IgG-treated SHR. Inhibition of COX (cyclo-oxygenase)-1 and COX-2, enzymes related to inflammatory pathways, decreased NA responses only in mesenteric resistance arteries of SHR treated with IgG. COX-2 expression and TXA2 (thromboxane A2) release were decreased in SHR treated with anti-TLR4 compared with IgG-treated SHR. Our results suggest that TLR4 activation contributes to increased BP, low-grade inflammation and plays a role in the augmented vascular contractility displayed by SHR.
authors.affiliation: Department of Pharmacology, University of Sao Paulo, Sao Paulo, SP, Brazil. gifacholi@yahoo.com.br
authors.forename: Gisele F
authors.initials: GF
authors.lastname: Bomfim
authors.forename: Rosangela A
authors.initials: RA
authors.lastname: Dos Santos
authors.forename: Maria Aparecida
authors.initials: MA
authors.lastname: Oliveira
authors.forename: Fernanda R
authors.initials: FR
authors.lastname: Giachini
authors.forename: Eliana H
authors.initials: EH
authors.lastname: Akamine
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.forename: Zuleica B
authors.initials: ZB
authors.lastname: Fortes
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Maria Helena C
authors.initials: MH
authors.lastname: Carvalho
mesh_terms: D000818:Animals; D001158:Arteries / Q000503:physiopathology; D001794:Blood Pressure; D051545:Cyclooxygenase 1 / Q000097:blood; D051546:Cyclooxygenase 2 / Q000097:blood; D011464:Epoprostenol / Q000097:blood; D005786:Gene Expression Regulation; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000097:blood; D008638:Mesenteric Arteries / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000097:blood; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014661:Vasoconstriction
chemical_list: D015850:Interleukin-6; D008565:Membrane Proteins; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D013928:Thromboxane A2; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat