Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release.

Abstract

Thrombosis and its complications are the leading cause of death in patients with diabetes. Metformin, a first-line therapy for type 2 diabetes, is the only drug demonstrated to reduce cardiovascular complications in diabetic patients. However, whether metformin can effectively prevent thrombosis and its potential mechanism of action is unknown. Here we show, metformin prevents both venous and arterial thrombosis with no significant prolonged bleeding time by inhibiting platelet activation and extracellular mitochondrial DNA (mtDNA) release. Specifically, metformin inhibits mitochondrial complex I and thereby protects mitochondrial function, reduces activated platelet-induced mitochondrial hyperpolarization, reactive oxygen species overload and associated membrane damage. In mitochondrial function assays designed to detect amounts of extracellular mtDNA, we found that metformin prevents mtDNA release. This study also demonstrated that mtDNA induces platelet activation through a DC-SIGN dependent pathway. Metformin exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing the release of free mtDNA, which induces platelet activation in a DC-SIGN-dependent manner. This study has established a novel therapeutic strategy and molecular target for thrombotic diseases, especially for thrombotic complications of diabetes mellitus.

• Authors: Guang Xin, Zeliang Wei, Chengjie Ji, Huajie Zheng, Jun Gu, Limei Ma, Wenfang Huang, Susan L Morris-Natschke, Jwu-Lai Yeh, Rui Zhang, Chaoyi Qin, Li Wen, Zhihua Xing, Yu Cao, Qing Xia, Yanrong Lu, Ke Li, Hai Niu, Kuo-Hsiung Lee, Wen Huang
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 36222 (11 02 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27805009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Hypoglycemic Agents
• Reactive Oxygen Species
• Metformin
• Electron Transport Complex I

Topics

• Animals
• Blood Platelets (drug effects, metabolism)
• DNA, Mitochondrial (metabolism)
• Diabetes Mellitus, Type 2 (complications)
• Electron Transport Complex I (metabolism)
• Hypoglycemic Agents (pharmacology)
• Male
• Metformin (pharmacology)
• Mice, Inbred C57BL
• Mitochondria (drug effects, genetics, metabolism)
• Platelet Activation (drug effects)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Thrombosis (complications, prevention & control)