Inhibition of TLR4 attenuates vascular dysfunction and oxidative stress in diabetic rats

Maria Alicia Carrillo-Sepulveda, Kathryn Spitler, Deepesh Pandey, Dan E. Berkowitz, Takayuki Matsumoto

Research output: Contribution to journalArticle

Abstract

Abstract: Hyperglycemia-induced reactive oxygen species (ROS) production plays a major role in the pathogenesis of diabetic vascular dysfunction. However, the underlying mechanisms remain unclear. Toll-like receptor 4 (TLR4), a key component of innate immunity, is known to be activated during diabetes. Therefore, we hypothesize that hyperglycemia activates TLR4 signaling in vascular smooth muscle cells (VSMCs) that triggers ROS production and causes vascular dysfunction. Rat mesenteric VSMCs exposed to high glucose (25 mmol/l) increased TLR4 expression and activated TLR4 signaling via upregulation of myeloid differentiation factor 88 (MyD88). TLR4 inhibitor CLI-095 significantly attenuated elevated levels of ROS and nuclear factor-kappa B (NF-κB) activity in VSMCs exposed to high glucose. Mesenteric arteries from streptozotocin-induced diabetic rats treated with CLI-095 (2 mg/kg/day) intraperitoneally for 2 weeks exhibited reduced ROS generation and attenuated noradrenaline-induced contraction. These results suggest that hyperglycemia-induced ROS generation and NF-κB activation in VSMCs are at least, in part, mediated by TLR4 signaling. Therefore, strategies to block TLR4 signaling pathways pose a promising avenue to alleviate diabetic-induced vascular complications. Key messages: High glucose-induced TLR4 activation in vascular smooth muscle cells.Inhibition of TLR4 attenuated high glucose-induced ROS production and NF-κB activity in VSMC.Suppression of TLR4 signaling attenuated mesenteric contraction in diabetic rat.

Original languageEnglish (US)
Pages (from-to)1341-1354
Number of pages14
JournalJournal of Molecular Medicine
Volume93
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Diabetes
  • High glucose
  • NF-κB
  • ROS
  • TLR4
  • Vascular smooth muscle cell

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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