Toll-like receptors 2 and 4 mediate hyperglycemia induced macrovascular aortic endothelial cell inflammation and perturbation of the endothelial glycocalyx

Roma Pahwa, Palanisamy Nallasamy, Ishwarlal Jialal

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Objectives Hyperglycemia-induced inflammation is central to the vascular complications in diabetes. Toll-like receptors (TLRs) are key players in regulating inflammatory responses. There are sparse data on the role of TLR2 and TLR4 in regulating human macrovascular aortic endothelial cells (HMAECs) inflammation and glycocalyx dysfunction under hyperglycemia. We examined the role of TLR2/4 in the above dysfunctions in HMAEC under high glucose (HG) conditions. Methods HMAECs were treated with high or normal glucose and TLR-2, TLR-4, MyD88, IRF3, TRIF, nuclear NF-κB p65, IL-8, IL-1β, TNF-α, MCP-1, ICAM-1, sVCAM-1, monocyte adhesion to HMAECs, heparan sulfate and hyaluronic acid were measured. Results HG upregulated TLR2 and TLR4 mRNA and protein and increased both MyD88 and non-MyD88 pathways, NF-κB p65, inflammatory biomediators, and monocyte adhesion to HMAECs. Heparan sulfate protein expression was reduced and hyaluronic acid secretion was increased on HG exposure. Inhibition of TLR2 and TLR4 signaling by inhibitory peptides and knockdown of TLR-2 and TLR-4 gene expression by siRNA attenuated HG induced inflammation, leukocyte adhesion and glycocalyx dysfunction. An increase in ROS paralleled the increase in TLR-2/4 and antioxidants treatment reduced TLR-2/4 expression and downstream inflammatory biomediators. Conclusion Thus hyperglycemia induces HMAEC inflammation and glycocalyx dysfunction through TLR-2/4 pathway activation via increased ROS.

Original languageEnglish (US)
Pages (from-to)563-572
Number of pages10
JournalJournal of Diabetes and its Complications
Volume30
Issue number4
DOIs
StatePublished - May 1 2016

Keywords

  • Glycocalyx
  • Hyperglycemia
  • Inflammation
  • Macrovascular complications
  • Toll-like receptors

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

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