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

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.

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis

“…It was reported that the replacement therapy of melatonin might contribute to restore insulin resistance of cardiomyocytes and skeletal muscle [46][47][48]. Withaferin A also has been demonstrated that it played an important role on improving high-fat diet-induced obesity and palmitic acid-induced endothelial insulin resistance through attenuation of oxidative stress and inflammation [49,50]. Levodopa is known as a precursor to dopamine.…”

Excessive Autophagy Activation and Increased Apoptosis Are Associated with Palmitic Acid-Induced Cardiomyocyte Insulin Resistance

“…Our results were similar with those from previous studies. For example, murine C2C12 myotubes and human umbilical vein endothelial cells (HUVECs) [ 33 ] required 750 μ M and 100 μ M PA, respectively, to induce IR. As these cells are from different species and tissues, the cellular metabolism is likely not the same; thus, differing levels of PA lead to IR.…”

Tetrahydroxy stilbene glucoside alleviates palmitic acid-induced inflammation and apoptosis in cardiomyocytes by regulating miR-129-3p/Smad3 signaling

“…Numerous studies have shown that PA is liable to induce an inflammatory response in a variety of cells [2, 15]. However, the protective effects of TSG on the PA-induced inflammatory response in H9c2 cardiomyocytes remained unknown.…”