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

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.

authors

Pahwa R,Nallasamy P,Jialal I

doi

10.1016/j.jdiacomp.2016.01.014

subject

Has Abstract

pub_date

2016-05-01 00:00:00

pages

563-72

issue

4

eissn

1056-8727

issn

1873-460X

pii

S1056-8727(16)00016-7

journal_volume

30

pub_type

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