Luteolin inhibits inflammatory response and improves insulin sensitivity in the endothelium

doi:10.1016/j.biochi.2010.11.002

Biochimie

Volume 93, Issue 3, March 2011, Pages 506-512

https://doi.org/10.1016/j.biochi.2010.11.002 Get rights and content

Abstract

Endothelial insulin resistance is tightly associated with diabetic cardiovascular complication, and it is well known that inflammation plays an important role in the development of insulin resistance. Luteolin, a flavonoid abundant in some medical and eatable plants, is a potent inhibitor of inflammation. It is also reported that luteolin exhibited some chemoprotection capability to the endothelial integrity. This study aims to clarify whether the anti-inflammatory potency of luteolin contributes to amelioration of insulin resistance in the endothelium. Palmitate (PA) stimulation markedly reduced insulin-mediated endothelium-dependent relaxation in rat aorta, while luteolin pretreatment effectively reversed the effects of palmitate in a concentration-dependent manner. PA stimulation also evoked inflammatory response in endothelial cells. When the cells were pretreated with luteolin, IKKβ phosphorylation were reduced, which, in turn, blocked the NF-κB activation through attenuating P65 phosphorylation. At the same time, it was also found that the gene over-expressions for TNF-α and IL-6 were also reduced by luteolin pretreatment. When endothelial cells were stimulated with PA, the insulin signaling cascades were impaired with reduced insulin-dependent production of NO. Again, pretreatment of luteolin could effectively reverse the effects of PA. Luteolin modulated the Ser/Thr phosphorylation of insulin receptor substrates-1 and restored downstream Akt/eNOS activation, resulting in increased NO production in the presence of insulin. In conclusion, these results suggested that luteolin ameliorated inflammation related endothelial insulin resistance in an IKKβ/IRS-1/Akt/eNOS-dependent pathway.

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.

References (29)

T. McLaughlin et al.
Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals
Metabolism
(2004)
Z. Gao et al.
Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex
J. Biol. Chem.
(2002)
A. Herschkovitz et al.
Common inhibitory serine sites phosphorylated by IRS-1 kinases, triggered by insulin and inducers of insulin resistance
J. Biol. Chem.
(2007)
T.A. Buchanan
Pancreatic beta-cell loss and preservation in type 2 diabetes
Clin. Ther.
(2003)
G. Zeng et al.
Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells
J. Clin. Invest.
(1996)
A.J. Lusis
Atherosclerosis
Nature
(2000)
J. Calles-Escandon et al.
Diabetes and endothelial dysfunction: a clinical perspective
Endocr. Rev.
(2001)
T. Kaneko et al.
Protective effect of flavonoids on endothelial cells against linoleic acid hydroperoxide-induced toxicity
Biosci. Biotechnol. Biochem.
(1999)
T. Kozakai et al.
Luteolin inhibits endothelin-1 secretion in cultured endothelial cells
Biosci. Biotechnol. Biochem.
(2005)
Y. Takano-Ishikawa et al.
Inhibitory effects of several flavonoids on E-selectin expression on human umbilical vein endothelial cells stimulated by tumor necrosis factor-alpha
Phytother. Res.
(2003)

Y.J. Jeong et al.

Attenuation of monocyte adhesion and oxidised LDL uptake in luteolin-treated human endothelial cells exposed to oxidised LDL

Br. J. Nutr.

(2007)

S. Junna et al.

Luteolin inhibits lysophosphatidylcholine-induced apoptosis in endothelial cells by a calcium/mitochondrion/caspase-dependent pathway

Planta Med.

(2010)

G.S. Hotamisligil et al.

Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance

Science

(1993)

M. Yuan et al.

Reversal of obesity- and diet-induced insulin resistance with sodium salicylates or targeted disruption of Ikk

Science

(2001)

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Research paperLuteolin inhibits inflammatory response and improves insulin sensitivity in the endothelium

Abstract

Research highlights

Introduction

Section snippets

Animals

Reagents

Luteolin restored PA-induced damaged relaxation of insulin in rat aortic rings

Discussion

Acknowledgements

Metabolism

J. Biol. Chem.

J. Biol. Chem.

Pancreatic beta-cell loss and preservation in type 2 diabetes

Clin. Ther.

Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells

J. Clin. Invest.

Atherosclerosis

Nature

Diabetes and endothelial dysfunction: a clinical perspective

Endocr. Rev.

Protective effect of flavonoids on endothelial cells against linoleic acid hydroperoxide-induced toxicity

Biosci. Biotechnol. Biochem.

Luteolin inhibits endothelin-1 secretion in cultured endothelial cells

Biosci. Biotechnol. Biochem.

Inhibitory effects of several flavonoids on E-selectin expression on human umbilical vein endothelial cells stimulated by tumor necrosis factor-alpha

Phytother. Res.

Attenuation of monocyte adhesion and oxidised LDL uptake in luteolin-treated human endothelial cells exposed to oxidised LDL

Br. J. Nutr.

Luteolin inhibits lysophosphatidylcholine-induced apoptosis in endothelial cells by a calcium/mitochondrion/caspase-dependent pathway

Planta Med.

Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance

Science

Reversal of obesity- and diet-induced insulin resistance with sodium salicylates or targeted disruption of Ikk

Science

Research paper
Luteolin inhibits inflammatory response and improves insulin sensitivity in the endothelium