Abstract
Endothelium dysfunction is one of the key events in diabetes, leading to progression of cardiovascular complications; however the underlying mechanism still remains elusive. TLR4 is a critical mediator of innate immunity, is expressed in vascular cells and has been reported to be activated during diabetes. We hypothesized that TLR4 signaling is activated in endothelial cells (EC) under hyperglycemic condition which causes endothelial dysfunction. TLR4 expression was robustly increased in EC primary cultures stimulated with 25mM high glucose for 48h [5.23±0.64 vs 2.95±0.37 normal glucose (NG), p<0.05] as well as MyD88, a downstream adapter protein of TLR4 signaling, (3.78±0.36 vs 1.44±0.55 NG, p<0.05). To test whether TLR4 contributes to endothelial dysfunction, streptozotocin (STZ)‐induced diabetic rats (65mg/kg, 5 weeks) were treated with a TLR4 signaling inhibitor (CLI‐095, 50ug/day) in the last 14 days. Aortas were isolated for functional studies and concentration‐responses to acetylcholine (Ach) were performed. Impaired Ach‐induced vascular relaxation observed in vessels from STZ rats compared to control (%47.17±1.74 vs. 75.05±4.34), p<0.05) was prevented with CLI‐095 treatment (%82.93±3.3, p<0.05). These results suggest that hyperglycemia upregulates endothelial TLR4 signaling which in turn contributes to endothelial dysfunction.
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