Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane

Abstract

Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates platelet aggregation. Although intensely studied, the mechanism underlying the relationship among hyperglycemia, TX generation, and platelet hyperactivity remains unclear. We sought to identify key signaling components that connect high levels of glucose to TX generation and to examine their clinical relevance. In human platelets, aldose reductase synergistically modulated platelet response to both hyperglycemia and collagen exposure through a pathway involving ROS/PLCγ2/PKC/p38α MAPK. In clinical patients with platelet activation (deep vein thrombosis; saphenous vein graft occlusion after coronary bypass surgery), and particularly those with diabetes, urinary levels of a major enzymatic metabolite of TX (11-dehydro-TXB 2 [TX-M]) were substantially increased. Elevated TX-M persisted in diabetic patients taking low-dose aspirin (acetylsalicylic acid, ASA), suggesting that such patients may have underlying endothelial damage, collagen exposure, and thrombovascular disease. Thus, our study has identified multiple potential signaling targets for designing combination chemotherapies that could inhibit the synergistic activation of platelets by hyperglycemia and collagen exposure. IntroductionAccelerated atherosclerosis and microvascular disease contribute to the morbidity and mortality associated with diabetes mellitus (DM) (1-3). Vascular inflammation, endothelial dysfunction associated with hyperglycemia, impaired fibrinolysis, and increased coagulation factors as well as abnormal platelet function are typical for DM, contributing to the increased thrombotic events and development of arteriosclerosis (4). Altered platelet function in DM, including altered adhesion and aggregation, may contribute to the pathogenesis of DM vascular complications by promoting microthrombus formation, contributing to enhanced risk of small vessel occlusions and accelerated atherothrombotic diseases (5, 6). Patients with type 2 DM (T2DM) exhibit platelet hyperreactivity both in vitro and in vivo, coupled with biochemical evidence of persistently increased thromboxane-dependent (TX-dependent) platelet activation (7,8). Despite many important studies, the mechanism by which platelets transduce glucose levels into enhanced TX generation independently of endothelial and other blood cell-derived factors remains unclear. Similarly, optimal antiplatelet therapy for DM patients remains to be achieved.Aldose reductase (AR) is the first enzyme of the polyol pathway, and it represents a minor source of glucose utilization, accounting for less than 3% of glucose consumption during euglycemia.

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

“…[57][58][59] Direct oxidation modification of VWF alone cannot explain the mechanism of increased uncleaved VWF levels in DM. Recent studies have suggested that the AR pathway through ROS production mediates platelet hyperactivity associated with hyperglycemia, 41 and the same pathway is responsible for increased thrombosis. 60 We now report for the first time that ROS production from AR can lead to accelerated thrombus formation through activation of c-Myc, inhibition of miR-24, and enhanced VWF production and secretion.…”

“…The activity of AR is increased during hyperglycemia and results in increased production of reactive oxygen species (ROS). 41 Interestingly, we found that the VWF level was significantly decreased in the cell pellets and medium of HUVECs cultured in high glucose when treated with an AR inhibitor (epalrestat) ( Figure 6A). Epalrestat significantly increased the miR-24 level in endothelial cells cultured in high glucose ( Figure 6B).…”

Vascular Complications of Diabetes

“…[172][173][174] In a retrospective study of >700 000 Veterans Affairs patients, using International Classification of Diseases-9 codes to identify diabetes mellitus, the risk of pulmonary embolism was 27% higher in the diabetic patients. 175 In a retrospective study of all patients admitted to a hospital with a venous thromboembolic event over a 2-year period, the age-adjusted risk for patients with type 1 or 2 diabetes mellitus was >2-fold that of patients without diabetes mellitus.…”

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

“…In addition, increased AKR1B1 activity depletes NADPH required for cellular antioxidant defenses and detoxifying systems (Pollak et al, 2007b), thus increasing susceptibility to oxidative stress (Pollak et al, 2007a;Ying, 2008). Moreover, AKR1B1 can elicit a proinflammatory and prothrombotic state in diabetes through oxidative stress (Tang et al, 2011) or Egr-1 hyperacetylation and activation (Vedantham et al, 2014). Consequently, the search for AKR1B1 inhibitors is an active field of research.…”