Hyperglycaemia-induced reciprocal changes in miR-30c and PAI-1 expression in platelets.
Type 2 diabetic mellitus (DM2) is associated with accelerated thrombotic complications and is characterized by high levels of plasminogen activator inhibitor-1 (PAI-1). Recent studies show that human platelets have high levels of miR-30c and synthesize considerable active PAI-1. The underlying mechanism of how PAI-1 expression is upregulated in DM2 is poorly understood. We now report that hyperglycaemia-induced repression of miR-30c increases PAI-1 expression and thrombus formation in DM2. Bioinformatic analysis and identification of miRNA targets were assessed using luciferase assays, quantitative real-time PCR and western blots in vitro and in vivo. The changes in miR-30c and PAI-1 levels were identified in platelets from healthy and diabetic individuals. We found that miR-30c directly targeted the 3' UTR of PAI-1 and negatively regulated its expression. miR-30c was negatively correlated with glucose and HbA1c levels in DM2. In HFD-fed diabetic mice, increasing miR-30c expression by lenti-miR-30c significantly decreased the PAI-1 expression and prolonged the time to occlusion in an arterial thrombosis model. Platelet depletion/reinfusion experiments generating mice with selective ablation of PAI-1 demonstrate a major contribution by platelet-derived PAI-1 in the treatment of lenti-miR-30c to thrombus formation. These results provide important implications regarding the regulation of fibrinolysis by platelet miRNA under diabetic mellitus.
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Mao
M
Luo
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Rong
R
Li
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Meiping
M
Ren
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Ni
N
Chen
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Xin
X
Deng
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Xiaoyong
X
Tan
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Yongjie
Y
Li
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Min
M
Zeng
Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
Yan
Y
Yang
Department of Endocrinology, the First Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Qin
Q
Wan
Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, China.|Laboratory for Cardiovascular Pharmacology of department of Pharmacology, the School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.|Department of Endocrinology, the First Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Jianbo
J
Wu
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*
C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human