title: Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3 inflammasome.
abstract: High glucose induced endothelial dysfunction is blamed for initiation of vascular complication in Type 2 diabetes mellitus. Rutin has been described in possessing comprehensive pharmacological activities, but the mechanism involved in endothelial protection through regulating oxidative stress and damage is still ambiguous. In the present study, rutin was evaluated in high glucose stimulated human umbilical vein endothelial cells (HUVECs) and high glucose diet-treated SD rats were applied to explored the molecular mechanism in rutin counteracting oxidative stress and damage. Firstly, 30 and 100μM rutin effectively increased HUVECs viability in high glucose challenge. Then we found that rutin could dose-dependently reduced high glucose mediated mRNA and protein expressions of Nox4. With Nox4 and Nox2 inhibitors, we further confirm that Nox4, but not Nox2, was responsible for reactive oxygen species (ROS) production in high glucose environment. Moreover, rutin and Nox4 inhibitor significantly ameliorated ROS generation and TXNIP, NLRP3, caspase-1 and IL-1β proteins expression in vivo. Furthermore, rutin substantially recovered nitric oxide production in HUVECs under high glucose condition. However, rutin could not inhibited inflammasome protein expressions and improved nitric oxide production in Nox4-overexpressed HUVECs under high glucose challenges. Finally, we found that rutin restored phenylephrine-mediated contractions and acetylcholine induced relaxations in aortic tissue of high glucose diet treated rats. In vitro, expressions of TXNIP, NLRP3, and caspase-1 in aortic tissue of high glucose diet treated rats were decreased under rutin administration. In summary, rutin may protect endothelial dysfunction through inhibiting Nox4 responsive oxidative stress and ROS-sensitive NLRP3 signaling pathway under high glucose stress both in vivo and vitro.
authors.affiliation: Department of Pharmacy, Maternal and Child Health Care Hospital of Zaozhuang, Zaozhuang, 277100, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Maternal and Child Health Care Hospital of Zaozhuang, Zaozhuang, 277100, China.
authors.forename: Qiu-Hong
authors.initials: QH
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Maternal and Child Health Care Hospital of Zaozhuang, Zaozhuang, 277100, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Sui
authors.affiliation: Department of Pharmacy, Maternal and Child Health Care Hospital of Zaozhuang, Zaozhuang, 277100, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Maternal and Child Health Care Hospital of Zaozhuang, Zaozhuang, 277100, China. Electronic address: pluxud@sina.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiu
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000633:toxicity; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012431:Rutin / Q000494:pharmacology*
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020011:Protective Agents; D017382:Reactive Oxygen Species; D012431:Rutin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D005947:Glucose
keywords: Endothelial dysfunction; High glucose; NLRP3 inflammasome; Nox4; ROS; Rutin