Abstract
Purpose: Luteolin exerts beneficial effects against obesity-associated comorbidities, although its influence on vascular dysfunction remains undetermined. We examined the effects of luteolin on endothelial dysfunction in a mouse model of diet-induced obesity.Methods: Standard diet (SD) or high-fat diet (HFD)-fed mice were treated daily with luteolin intragastrically. After 8 weeks, body and epididymal fat weight, as well as blood cholesterol, glucose, and triglycerides were evaluated. Endothelium-dependent relaxations of resistance mesenteric vessels was assessed by a concentration-response curve to acetylcholine, repeated upon Nw-nitro-L-arginine methylester (L-NAME) or ascorbic acid infusion to investigate the influence of nitric oxide (NO) availability and reactive oxygen species (ROS) on endothelial function, respectively. Intravascular ROS production and TNF levels were measured by dihydroethidium dye and ELISA, respectively. Endothelial NO synthase (eNOS) and superoxide dismutase 1 (SOD1), as well as microRNA-214-3p expression were examined by Western blot and RT-PCR assays, respectively.Results: HFD animals displayed elevated body weight, epididymal fat weight and metabolic indexes. Endothelium-dependent relaxation was resistant to L-NAME and enhanced by ascorbic acid, which restored also the inhibitory effect of L-NAME, suggesting a ROS-dependent reduction of NO availability in HFD vessels. Moreover, media-lumen ratio, intravascular superoxide anion and TNF levels were increased, while vascular eNOS, SOD1, and microRNA-214-3p expression were decreased. In HFD mice, luteolin counteracted the increase in body and epididymal fat weight, and metabolic alterations. Luteolin restored vascular endothelial NO availability, normalized the media-lumen ratio, decreased ROS and TNF levels, and normalized eNOS, SOD1 and microRNA-214-3p expression.Conclusion: Luteolin prevents systemic metabolic alterations and vascular dysfunction associated with obesity, likely through antioxidant and anti-inflammatory mechanisms.
Highlights
Obesity represents a major public health and economic problem of global significance that reflects behavioral changes in modern society, including the greater intake of fat-rich food and sedentary lifestyle (World Health Organization [WHO] and Global Health Observatory [GHO], 2014)
Luteolin prevents systemic metabolic alterations and vascular dysfunction associated with obesity, likely through antioxidant and anti-inflammatory mechanisms
In animals fed with Standard diet (SD), luteolin did not modify the pattern of body weight gain throughout 8 weeks, as compared with control SD animals (Figure 1A)
Summary
Obesity represents a major public health and economic problem of global significance that reflects behavioral changes in modern society, including the greater intake of fat-rich food and sedentary lifestyle (World Health Organization [WHO] and Global Health Observatory [GHO], 2014). Endothelial dysfunction is generally characterized by an increased level of vascular wall oxidative stress, supported mainly by reactive oxygen species (ROS). This leads to a greater NO consumption, resulting in an impairment of endothelial-dependent vasorelaxation (Furukawa et al, 2004; Heistad, 2006; Munzel et al, 2010; Sena et al, 2013). HFD-induced obesity has been reported to alter vascular reactivity (vasoconstriction) and to increase cardiac mass in mice (Calligaris et al, 2013), along with an increase in both inflammation and oxidative stress, strongly implicated in the onset of endothelial dysfunction (GamezMendez et al, 2015)
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