Toll-like receptor 4 (TLR4) impairs nitric oxide contributing to Angiotensin II-induced cavernosal dysfunction

Kenia P. Nunes, Gisele F. Bomfim, Haroldo A. Toque, Theodora Szasz, R. Clinton Webb

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Aim Angiotensin II (AngII), a corpus cavernosum (CC) constrictor peptide, modulates Toll like receptor (TLR) expression, a key element of the innate immune system, contributing to impaired vascular function in pathological conditions. However, it is unknown whether TLR4 is involved in AngII-induced erectile dysfunction. In this study, we investigated whether TLR4 plays a role in cavernosal dysfunction caused by AngII upregulation. Material and methods Cavernosal smooth muscle cells (CSMC) from C57/BL6 mice were treated with AngII (0.1 μM) or bacterial LPS (50 ng/ml) for 12–24 h and TLR4 expression was assessed. Mice were infused with AngII (90 ng/min, 28 days) and treated with anti-TLR4 antibody (0.1 mg/daily, i.p.) for the last 14 days of the treatment. CC tissue was used for functional studies and for Western blotting. Nitric Oxide Synthase (NOS) activity was measured by conversion of [3H]-L-arginine to [3H]-L-citrulline, systemic TNF-α levels by ELISA, and reactive oxygen species (ROS) by immunofluorescence. Key findings We report upregulation of TLR4 in CSMC following AngII or LPS stimulation. In AngII-infused mice, chronic treatment with anti-TLR4 antibody (28 ± 2.1%) attenuates adrenergic CC contraction, which also ameliorates nitrergic (68.90 ± 0.21 vs. 51.07 ± 0.63, 8 Hz, AngII-infused mice treated vs. non-treated). Decreased endothelial NOS expression, reduced NOS activity, and augmented levels of TNF-α, and ROS were found following AngII-infusion. These alterations were prevented, or at least decreased by anti-TLR4 antibody treatment. Significance Inhibition of TLR4 ameliorates AngII-impaired cavernosal relaxation, decreases TNF-α levels, and restores NO bioavailability, demonstrating that TLR4 partly mediates AngII-induced cavernosal dysfunction.

Original languageEnglish (US)
Pages (from-to)219-226
Number of pages8
JournalLife sciences
Volume191
DOIs
StatePublished - Dec 15 2017

Keywords

  • Angiotensin-II
  • Nitric oxide
  • TLR4
  • TNF-α

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Toll-like receptor 4 (TLR4) impairs nitric oxide contributing to Angiotensin II-induced cavernosal dysfunction'. Together they form a unique fingerprint.

  • Cite this