AUTHOR=Gentile Daniela , Fornai Matteo , Pellegrini Carolina , Colucci Rocchina , Benvenuti Laura , Duranti Emiliano , Masi Stefano , Carpi Sara , Nieri Paola , Nericcio Anna , Garelli Francesca , Virdis Agostino , Pistelli Laura , Blandizzi Corrado , Antonioli Luca 

TITLE=Luteolin Prevents Cardiometabolic Alterations and Vascular Dysfunction in Mice With HFD-Induced Obesity

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01094

DOI=10.3389/fphar.2018.01094

ISSN=1663-9812

ABSTRACT=<p><bold>Purpose:</bold> 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.</p><p><bold>Methods:</bold> 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 N<sup>w</sup>-nitro-L-arginine methylester (<sc>L</sc>-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.</p><p><bold>Results:</bold> HFD animals displayed elevated body weight, epididymal fat weight and metabolic indexes. Endothelium-dependent relaxation was resistant to <sc>L</sc>-NAME and enhanced by ascorbic acid, which restored also the inhibitory effect of <sc>L</sc>-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.</p><p><bold>Conclusion:</bold> Luteolin prevents systemic metabolic alterations and vascular dysfunction associated with obesity, likely through antioxidant and anti-inflammatory mechanisms.</p>