Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats

G. F. Bomfim, C. Echem, C. B. Martins, T. J. Costa, S. M. Sartoretto, R. A. Dos Santos, M. A. Oliveira, E. H. Akamine, Z. B. Fortes, R. C. Tostes, R Clinton Webb, M. H.C. Carvalho

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Aims 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.

Main methods SHR and Wistar rats were treated with anti-TLR4 antibody (1 μg/day) or unspecific IgG for 15 days (i.p.).

Key findings 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.

Significance Together, these results suggest that TLR4 is a key player in hypertension and vascular inflammatory process by a NFκB signaling pathway.

Original languageEnglish (US)
Pages (from-to)1-7
Number of pages7
JournalLife sciences
Volume122
DOIs
StatePublished - Feb 1 2015

Keywords

  • Hypertension
  • Innate immune response
  • NF-κB
  • Toll-like receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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    Bomfim, G. F., Echem, C., Martins, C. B., Costa, T. J., Sartoretto, S. M., Dos Santos, R. A., Oliveira, M. A., Akamine, E. H., Fortes, Z. B., Tostes, R. C., Webb, R. C., & Carvalho, M. H. C. (2015). Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats. Life sciences, 122, 1-7. https://doi.org/10.1016/j.lfs.2014.12.001