title: 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-TXB2 [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.
authors: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Wai Ho
authors: WH
authors: Tang
authors: Jeremiah
authors: J
authors: Stitham
authors: Scott
authors: S
authors: Gleim
authors: Concetta
authors: C
authors: Di Febbo
authors: Ettore
authors: E
authors: Porreca
authors: Cristiano
authors: C
authors: Fava
authors: Stefania
authors: S
authors: Tacconelli
authors: Marta
authors: M
authors: Capone
authors: Virgilio
authors: V
authors: Evangelista
authors: Giacomo
authors: G
authors: Levantesi
authors: Li
authors: L
authors: Wen
authors: Kathleen
authors: K
authors: Martin
authors: Pietro
authors: P
authors: Minuz
authors: Jeffrey
authors: J
authors: Rade
authors: Paola
authors: P
authors: Patrignani
authors: John
authors: J
authors: Hwa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000097:blood*; D001241:Aspirin / Q000008:administration & dosage; D001786:Blood Glucose / Q000378:metabolism*; D016022:Case-Control Studies; D003094:Collagen / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D048308:Mitogen-Activated Protein Kinase 14 / Q000097:blood; D008954:Models, Biological; D018384:Oxidative Stress; D051966:Phospholipase C gamma / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000097:blood; D017382:Reactive Oxygen Species / Q000097:blood; D015398:Signal Transduction; D013931:Thromboxanes / Q000097:blood*; D020246:Venous Thrombosis / Q000097:blood
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; D017382:Reactive Oxygen Species; D013931:Thromboxanes; D003094:Collagen; D000449:Aldehyde Reductase; D011493:Protein Kinase C; D048308:Mitogen-Activated Protein Kinase 14; D051966:Phospholipase C gamma; D001241:Aspirin