Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release.
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.
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.|Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
Guang
G
Xin
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Zeliang
Z
Wei
Clinical Laboratory, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
Chengjie
C
Ji
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.|Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
Huajie
H
Zheng
Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Jun
J
Gu
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Limei
L
Ma
Clinical Laboratory, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
Wenfang
W
Huang
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.
Susan L
SL
Morris-Natschke
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Jwu-Lai
JL
Yeh
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Rui
R
Zhang
Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Chaoyi
C
Qin
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.|Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
Li
L
Wen
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Zhihua
Z
Xing
Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Yu
Y
Cao
Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
Qing
Q
Xia
Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Sichuan University, Chengdu, Sichuan, China.
Yanrong
Y
Lu
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Ke
K
Li
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.|College of Mathematics, Sichuan University, Chengdu, Sichuan, China.
Hai
H
Niu
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.|Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
Kuo-Hsiung
KH
Lee
Laboratory of Ethnopharmacology, Institute for Nanobiomedical Technology and Membrane Biology, Regenerative Medicine Research Center, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Wen
W
Huang
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D042967:Electron Transport Complex I / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013927:Thrombosis / Q000150:complications / Q000517:prevention & control*
D004272:DNA, Mitochondrial; D007004:Hypoglycemic Agents; D017382:Reactive Oxygen Species; D008687:Metformin; D042967:Electron Transport Complex I