Research paperLuteolin inhibits inflammatory response and improves insulin sensitivity in the endothelium
Research highlights
► Palmitate (PA) induced inflammation-related insulin resistance in the endothelium. ► Pretreatment of luteolin effectively reversed the effects of PA. ► Luteolin inhibited inflammatory response and improved the insulin sensitivity. ► Its action depended on an IKKβ/IRS-1/Akt/eNOS pathway.
Introduction
Type 2 diabetes represents approximately 90% of all cases of diabetes. Cardiovascular complications greatly increased the morbidity and mortality of type 2 diabetic patients. One of the hallmarks of diabetic cardiovascular complications is endothelial dysfunction, which is an important reason for the reduced production and weakened function of nitric oxide (NO), a vasodilator and endothelial homeostatic agent. It is well known that insulin resistance plays an important role in the development of diabetes and it is tightly associated with diabetic cardiovascular complication [1], [2]. One of the insulin’s physiological functions is to promote vasodilatation by increasing NO production in the vasculature. The production of NO depends primarily on the activation of the insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/PI3K/Akt signaling cascades [3]. In the vascular tissues, insulin resistance is characterized by selective impairment in PI3K-dependent insulin signaling cascades. Meanwhile, the reduced NO synthesis leads to endothelial dysfunction, which is a pivotal step in the pathogenesis of cardiovascular disease involved in insulin resistance or diabetes [4], [5].
Luteolin (3′, 4′, 5, 7-tetrahydroxyflavone), a naturally occurring polyphenol flavonoid, is abundant in plants worldwide and possesses a variety of biological activities. Many studies have been done to investigate its modulation of endothelial function. Luteolin could protect endothelial cells against oxidative stress [6], inhibit endothelin-1 (ET-1) secretion [7], monocyte adhesion and E-selectin expression in endothelial cells [8], [9]. Our previous study has also reported that luteolin could inhibit lysophosphatidylcholine-induced apoptosis in endothelial cells [10]. Above-mentioned evidences well demonstrate that luteolin owns chemical protection capability toward the endothelium. But up to now, little is known about its biological modulation toward insulin action in the endothelium, especially in the endothelial insulin-resistant states. It has been reported that pro-inflammatory cytokine TNF-α was able to induce insulin resistance and that sodium salicylate inhibited insulin resistance by inhibition of IKKβ/NF-κB activation. Therefore, there is a causal link between inflammation and insulin resistance [11], [12]. Luteolin is a potent inhibitor of inflammation [13], [14], but it is still unknown whether its anti-inflammatory potency contributes to amelioration of insulin resistance. Because insulin resistance-induced endothelial dysfunction is a key event in cardiovascular disease, this study is to investigate the effect of luteolin on PA-induced insulin resistance in endothelium and to better understand the relative mechanism underlying its regulation of insulin signaling transduction. Our results demonstrated that luteolin ameliorated PA-induced endothelial dysfunction by restoring insulin sensitivity through an IKKβ/IRS-1/Akt/eNOS-dependent pathway.
Section snippets
Animals
Sprague-Dawley rats (weight 250–300 g), supplied by the Laboratory Animal Center of Zhejiang Province, were used for the study of aorta contraction. The care and treatment of these rats was maintained in accordance with the Provisions and General Recommendation of Chinese Experimental Animals Administration Legislation.
Reagents
Luteolin (purity = 98%) was purchased from Shaanxi huike Plant Co., Ltd. (Xian, China) and dissolved in DMSO (0.1% w/v). Insulin was from Sigma (St. Louis, MO, USA). Palmitate (PA)
Luteolin restored PA-induced damaged relaxation of insulin in rat aortic rings
To investigate the effects of luteolin on insulin functions on the vessel, we first studied whether the insulin-mediated vessel relaxation was endothelium-dependent. In the intact aorta ring precontracted with phenylephrine (10−6 M), vessel relaxation increased with increasing levels of insulin from 10−9 to 10−6 M. There was an 89% relaxing rate in the presence of 10−6 M insulin. When the endothelium was denuded by mechanical removal, the insulin-mediated relaxation was dramatically reduced. There
Discussion
Obesity is one of the most important identified factors contributing to insulin resistance [15]. Free fatty acids (FFAs), levels of which are elevated in obesity, cause insulin resistance in liver and skeletal muscle [16], [17]. Palmitic acid is a major component of dietary saturated fat, representing up to 20% of the total serum FFAs. It has been shown to be present in a high percentage of atherosclerotic lesions [18], [19]. One of the key vascular actions of insulin is to promote
Acknowledgements
This study was supported by the Fundamental Research Funds for the Central Universities from Ministry of Education of the People’s Republic of China (No. ZJ10041). We are grateful to Dr. Zhuang Shufei (Stowers Institute for Medical Research, Kansas City, USA) for her careful checking the language of the manuscript.
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