Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor
Title | Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Xiang Y, Cheng J, Wang D, Hu X, Xie Y, Stitham J, Atteya G, Du J, Tang WHo, Lee SHee, Leslie K, Spollett G, Liu Z, Herzog E, Herzog RI, Lu J, Martin KA, Hwa J |
Journal | Blood |
Volume | 125 |
Issue | 22 |
Pagination | 3377-87 |
Date Published | 2015 May 28 |
ISSN | 1528-0020 |
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. |
DOI | 10.1182/blood-2015-01-620278 |
Alternate Journal | Blood |
PubMed ID | 25814526 |
PubMed Central ID | PMC4447857 |
Grant List | R01 DK101984 / DK / NIDDK NIH HHS / United States R01 HL074190 / HL / NHLBI NIH HHS / United States R01 HL091013 / HL / NHLBI NIH HHS / United States R01 HL109233 / HL / NHLBI NIH HHS / United States R01 HL115247 / HL / NHLBI NIH HHS / United States R01 HL119529 / HL / NHLBI NIH HHS / United States R01 HL122815 / HL / NHLBI NIH HHS / United States R03 DK100709 / DK / NIDDK NIH HHS / United States U54 HL117798 / HL / NHLBI NIH HHS / United States UL1 TR000142 / TR / NCATS NIH HHS / United States |