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Research Article

Vildagliptin inhibits high free fatty acid (FFA)-induced NLRP3 inflammasome activation in endothelial cells

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Pages 1067-1074 | Received 01 Nov 2018, Accepted 22 Dec 2018, Published online: 04 Apr 2019
 

Abstract

Elevated free fatty acids (FFAs) are a risk factor for type 2 diabetes. Endothelial dysfunction induced by high levels of FFAs is one of the mechanisms related to the progression of diabetes. In clinical diabetes care, DPP-4 inhibitors have been shown to be effective in reducing glucose levels. In this study, we investigated the molecular mechanism of the clinically available DPP-4 inhibitor vildagliptin in the protection of FFA-induced endothelial dysfunction. Treatment of endothelial cells with vildagliptin inhibits FFA-induced cellular LDH release and generation of ROS. Vildagliptin also reverses FFA-induced reduced levels of GSH and elevated expression of the FFA-associated NAPHD oxidase protein NOX-4. Moreover, vildagliptin ameliorates the reduction in mitochondrial potential triggered by FFAs. Mechanistically, we show that vildagliptin suppresses FFA-induced expression of proteins of the NLRP3 inflammasome complex, including NLRP3, ASC, p20 and HMGB-1, and mitigates FFA-induced inactivation of the AMPK pathway. Consequently, vildagliptin inhibits production of two cytokines that are favored by NLRP3 inflammasome machinery: IL-1β and IL-18. Finally, we demonstrate that vildagliptin ameliorates FFA-induced reduced eNOS, indicating its protective role against endothelial dysfunction. Collectively, we conclude that the protective role of vildagliptin in endothelial cells is mediated via suppression of the AMPK-NLRP3 inflammasome-HMGB-1 axis pathway. These findings imply that the anti-diabetic drug vildagliptin possesses dual therapeutic applications in lowering glucose and improving vascular function.

Disclosure statement

None of the authors of this article have any conflicts of interest that require disclosure.