THROMBOSIS AND HEMOSTASIS Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor

In conjunction with the rising incidence of obesity, the prevalence of diabetes mellitus (DM) is rapidly increasing. Globally, the prevalence of DM is estimated to increase from 382 million individuals in 2013 to 592 million individuals by 2035 and is mainly attributable to type 2 DM (T2DM), which represents;90% to 95%of all cases. At present, .27.9 million Americans (11.8% of total population) have DM (diagnosed and undiagnosed), and .90 million (38.2%) have prediabetes (abnormal fasting glucose). Within the vasculature, DM impairs endothelial cell function and induces platelet hyperactivity. As such, DM serves as a major risk factor for cardiovascular disease and stroke, with more than half of all diabetic patients dying fromcardiovascular-related thrombosis (acute coronary syndrome or cerebrovascular event). Despite such pervasiveness, the underlying mechanisms for the thrombotic complications in DM are not fully understood. von Willebrand factor (VWF) is a key blood component that initiates thrombosis and is highly predictive of adverse thrombotic cardiovascular events in DM patients. Expressed in endothelial cells andmegakaryocytes (platelet precursor cells), VWF plays a crucial role in maintaining normal hemostasis and contributes to thrombotic disorders following endothelial and platelet dysfunction. VWF is a large multidomain plasma glycoprotein that is critical for normal platelet tethering during hemostasis. In response to blood shear forces, VWF unfolds from its inactive globular conformation into an active string-like form that can specifically recruit platelets. The multimeric size of VWF is a primary determinant of its platelet-tethering function and is proteolytically regulated by the plasma metalloprotease ADAMTS13, which is responsible for the degradation of large, thrombogenic VWF multimers. The importance of ADAMTS13 in maintaining the balance of VWF multimeric size is illustrated by its role in a number of hematologic disorders, including (1) the idiopathic form of thrombotic thrombocytopenic purpura, a blood-clotting disorder in which antibodymediated inhibition or congenital deficiency of ADAMTS13 causes spontaneous platelet aggregation via accumulation of uncleaved ultralarge high-molecular-weight VWFmultimers and (2) some cases of vonWillebrand disease, type 2A, inwhichVWF ismore rapidly cleaved by ADAMTS13, resulting in a bleeding phenotype. Given the importance of VWF in regulation of thrombosis, the molecular mechanism regulating VWF expression and secretion, particularly in DM patients, remains unexplored.