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Int J Biol Sci 2019; 15(5):1010-1019. doi:10.7150/ijbs.29680

Research Paper

Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy

Fan Yang1, Ying Qin2, Yueqiu Wang1, Songyan Meng3, Huimin Xian4, Hui Che1,2, Jie Lv1, Yang Li1, Yahan Yu5, Yunlong Bai2,5✉, Lihong Wang1,2✉

1. Department of Endocrinology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China;
2. Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China;
3. Department of Geriatrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China;
4. Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China;
5. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.

Abstract

Metformin is a widely used antidiabetic drug for type 2 diabetes that can play a cardioprotective role through multiple pathways. It is a recognized agonist of AMP-activated protein kinase (AMPK) that blocks mitochondrial complex I. The NLRP3 inflammasome has been demonstrated to be activated in diabetic cardiomyopathy (DCM). However, the role of metformin in regulating the NLRP3 signaling pathway in DCM remains unclear. It has been reported that AMPK can inhibit NLRP3 by activating autophagy. The aim of this study was to investigate whether metformin can inhibit the NLRP3 inflammasome by activating the AMPK/mTOR pathway in DCM. In this study, streptozotocin-induced C57BL/6 mice and high glucose-treated primary cardiomyocytes from neonatal mice were treated with metformin or an AMPK inhibitor compound C. Echocardiography, hematoxylin-eosin and Masson staining showed that the function and morphology of the diabetic hearts were improved after metformin treatment, whereas these parameters deteriorated after intervention with an AMPK inhibitor. Immunohistochemical staining, immunofluorescence staining and western blot assays indicated that the expression levels of mTOR, NLRP3, caspase-1, IL-1β and GSDMD-N were decreased in the diabetic model treated with metformin and were reversed after the administration of an AMPK inhibitor in vivo and in vitro. Mechanistically, our results demonstrated that metformin can activate AMPK, thus improving autophagy via inhibiting the mTOR pathway and alleviating pyroptosis in DCM. Thus, we provide novel information for the treatment of DCM.

Keywords: metformin, AMPK, autophagy, NLRP3 inflammasome, diabetic cardiomyopathy

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Yang F, Qin Y, Wang Y, Meng S, Xian H, Che H, Lv J, Li Y, Yu Y, Bai Y, Wang L. Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy. Int J Biol Sci 2019; 15(5):1010-1019. doi:10.7150/ijbs.29680. Available from http://www.ijbs.com/v15p1010.htm