title: Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor.
abstract: An elevated level of von Willebrand factor (VWF) in diabetic patients is associated with increased risk of thrombotic cardiovascular events. The underlying mechanism of how VWF expression is upregulated in diabetes mellitus is poorly understood. We now report that hyperglycemia-induced repression of microRNA-24 (miR-24) increases VWF expression and secretion in diabetes mellitus. In diabetic patients and diabetic mouse models (streptozotocin/high-fat diet-induced and db/db mice), miR-24 is reduced in both tissues and plasma. Knockdown of miR-24 in mice leads to increased VWF mRNA and protein levels and enhanced platelet tethering (spontaneous thrombosis). miR-24 tightly controls VWF levels through pleiotropic effects, including direct binding to the 3' untranslated region of VWF and targeting FURIN and the histamine H1 receptor, known regulators of VWF processing and secretion in endothelial cells. We present a novel mechanism for miR-24 downregulation through hyperglycemia-induced activation of aldose reductase, reactive oxygen species, and c-Myc. These findings support a critical role for hyperglycemic repression of miR-24 in VWF-induced pathology. miR-24 represents a novel therapeutic target to prevent adverse thrombotic events in patients with diabetes mellitus.
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Yaozu
authors: Y
authors: Xiang
authors: Department of Genetics, Yale Stem Cell Center.
authors: Jijun
authors: J
authors: Cheng
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Dandan
authors: D
authors: Wang
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Xiaoyue
authors: X
authors: Hu
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Yi
authors: Y
authors: Xie
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Jeremiah
authors: J
authors: Stitham
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Gourg
authors: G
authors: Atteya
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Jing
authors: J
authors: Du
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Wai Ho
authors: WH
authors: Tang
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Seung Hee
authors: SH
authors: Lee
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Kristen
authors: K
authors: Leslie
authors: Section of Endocrinology and Metabolism, Yale Diabetes Center, and.
authors: Geralyn
authors: G
authors: Spollett
authors: Section of Endocrinology and Metabolism, Yale Diabetes Center, and.
authors: Zejian
authors: Z
authors: Liu
authors: Section of Pulmonary Medicine, Yale University School of Medicine, New Haven, CT.
authors: Erica
authors: E
authors: Herzog
authors: Section of Endocrinology and Metabolism, Yale Diabetes Center, and.
authors: Raimund I
authors: RI
authors: Herzog
authors: Department of Genetics, Yale Stem Cell Center.
authors: Jun
authors: J
authors: Lu
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: Kathleen A
authors: KA
authors: Martin
authors: Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center.
authors: John
authors: J
authors: Hwa
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism*
chemical_list: C543845:MIRN24 microRNA, human; D035683:MicroRNAs; D014841:von Willebrand Factor