Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane
Wai Ho Tang, … , Paola Patrignani, John Hwa
Wai Ho Tang, … , Paola Patrignani, John Hwa
Published October 17, 2011
Citation Information: J Clin Invest. 2011;121(11):4462-4476. https://doi.org/10.1172/JCI59291.
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Research Article Hematology

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

Wai Ho Tang, Jeremiah Stitham, Scott Gleim, Concetta Di Febbo, Ettore Porreca, Cristiano Fava, Stefania Tacconelli, Marta Capone, Virgilio Evangelista, Giacomo Levantesi, Li Wen, Kathleen Martin, Pietro Minuz, Jeffrey Rade, Paola Patrignani, John Hwa

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Figure 2

Glucose-induced platelet activation and aggregation in response to 1 μg/ml collagen or 1 μM ADP.

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Glucose-induced platelet activation and aggregation in response to 1 μg/...
The platelet suspensions were incubated with 5.5 mmol/l, 15 mmol/l, or 25 mmol/l glucose for 90 minutes. Percentage of light transmission, an index of platelet aggregation, was measured in platelet suspensions in response to (A) 1 μg/ml collagen or (B) 1 μM ADP for 10 minutes. (C) Quantification of data presented as percentage of light transmission. Data are expressed as mean ± SD (n = 5 HS). ***P < 0.001 and **P < 0.01 compared with 5.5 mM glucose; #P < 0.05 compared with 15 mM glucose. P selectin translocation to membrane was assessed by flow cytometry after stimulation with (D) 1 μg/ml collagen or (E) 1 μM ADP. The representative overlay plots were presented as the number of events over the log of associated fluorescence (baseline refers to the group without collagen or ADP stimulation). (F) Quantification of data presented as MFI. Data are expressed as mean ± SD (n = 5 HS). ***P < 0.001 and **P < 0.01 compared with 5.5 mM glucose; #P < 0.05 compared with 15 mM glucose; §§§P < 0.001 compared with baseline.