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.
View: Text | PDF
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

×

Figure 6

AR contributes to oxidative stress in collagen-stimulated platelets.

Options: View larger image (or click on image) Download as PowerPoint
AR contributes to oxidative stress in collagen-stimulated platelets. Pla...
Platelet suspensions were incubated with NG or HG for 90 minutes in the presence or absence of 10 μmol/l epalrestat, 1 mmol/l NAC, and 100 μmol/l apocynin (Apo). (A) Washed platelets were incubated with 1 μmol/l ROS/Superoxide Detection Mix for 60 minutes at 37°C in the presence or absence of 1 μg/ml collagen for 10 minutes. The quantification of data for ROS is shown in the left panel, and that for superoxide is shown in the right panel. Data are expressed as mean ± SD (n = 5 HS). ***P < 0.001, **P < 0.01, and *P < 0.05 compared with values incubated in NG alone; ###P < 0.001, ##P < 0.01, and #P < 0.05 compared with values in NG with the addition of 1 μg/ml collagen; §§§P < 0.001 compared with values in HG with the addition of 1 μg/ml collagen. (B) Aggregation expressed as the percentage of light transmission and measured in platelet suspensions under NG or HG conditions. (C) Levels of TXB2 assayed in the supernatant. Data are expressed as mean ± SD (n = 5 HS). ***P < 0.001 compared with values incubated in NG with the addition of 1 μg/ml collagen; ###P < 0.001 compared with values in HG with the addition of 1 μg/ml collagen.