Activation of inflammatory pathways via
reactive oxygen species (ROS) by
free fatty acids (FFA) in
obesity gives rise to
insulin resistance and endothelial dysfunction.
Withaferin A (WA), possesses both
antioxidant and anti-inflammatory properties and therefore would be a good strategy to suppress
palmitic acid (PA)-induced oxidative stress and
inflammation and hence,
insulin resistance and dysfunction in the endothelium. Effect of WA on PA-induced
insulin resistance in human umbilical vein endothelial cells (HUVECs) was determined by evaluating
insulin signaling mechanisms whilst effect of this drug on PA-induced endothelial dysfunction was determined in
acetylcholine-mediated relaxation in isolated rat aortic preparations. WA significantly inhibited ROS production and
inflammation induced by PA. Furthermore, WA significantly decreased TNF-α and
IL-6 production in endothelial cells by specifically suppressing IKKβ/NF-κβ phosphorylation. WA inhibited
inflammation-stimulated IRS-1
serine phosphorylation and improved the impaired
insulin PI3-K signaling, and restored the decreased
nitric oxide (NO) production triggered by PA. WA also decreased
endothelin-1 and
plasminogen activator inhibitor type-1 levels, and restored the impaired endothelium-mediated vasodilation in isolated aortic preparations. These findings suggest that WA inhibited both ROS production and
inflammation to restore impaired
insulin resistance in cultured endothelial cells and improve endothelial dysfunction in rat aortic rings.