Withaferin A protects against palmitic acid-induced endothelial insulin resistance and dysfunction through suppression of oxidative stress and inflammation.

Kalaivani Batumalaie,Munavvar Zubaid Abdul Sattar,Nor Azizan Abdullah,Dharmani Devi Murugan,Muhammad Arif Amin

doi:10.1038/srep27236

Kalaivani Batumalaie, Munavvar Zubaid Abdul Sattar + Show 3 more

Open Access

https://doi.org/10.1038/srep27236

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Abstract

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.

Highlights

Endothelial dysfunction characterized by impairment of endothelium-dependent vasodilatation can result from an increase in reactive oxygen species (ROS) and inflammation which will lead to a loss of insulin-stimulated nitric oxide (NO) secretion
In order to investigate the effect of Withaferin A (WA) alone on Human umbilical vein endothelial cells (HUVECs), the cells were treated with different concentrations of WA (0.5, 1, 1.5, 2, 4, 8 μM) and assessed for the number of viable cells after 24 h as the viability declined
This result should be interpreted with carefulness as it is known that sometimes cell culture imposes a state of oxidative stress on cells that can lead to senescence, cell death, or adaptation[13,14]

Summary

Introduction

Endothelial dysfunction characterized by impairment of endothelium-dependent vasodilatation can result from an increase in ROS and inflammation which will lead to a loss of insulin-stimulated nitric oxide (NO) secretion. Increased plasminogen activator inhibitor type-1 (PAI-1) and endothelin-1 (ET-1) secretion contribute to endothelial dysfunction resulting in more expression of adhesion molecules and progression of pro-thrombotic state[3,5]. Reduced bioavailability of NO, in part due to increased oxidative stress and inflammation, appears to play a crucial role in the endothelial dysfunction associated with obesity. Since oxidative stress and inflammation are purported to play key roles in the development of endothelial insulin resistance and dysfunction in diseases where FFAs are elevated, this study tested the beneficial effect of WA on these pathological conditions associated with PA-induced oxidative stress and inflammation

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