Diabetes mellitus is a major cause of cardiovascular morbidity and mortality in the United States. Enhanced platelet function participates in the pathogenesis of vascular complications. We have recently observed that there is significant thromboxane release from diabetic platelets particularly during hyperglycemia and that aldose reductase may play a significant role in promoting platelet hyperactivity. Our goals are to discover the mechanism by which hyperglycemia is transduced into thromboxane release contributing to diabetic platelet dysfunction. Through three Specific Aims we will initially addres the role of aldose reductase in transducing this high glucose signal to platelet dysfunction (Specific Aim #1).
Specific Aim #2 will determine whether this signaling process may contribute to aspirin insensitivity that is often observed among diabetic patients, and Specific Aim #3 will assess how newly discovered genetic variants may influence both the response to hyperglycemia and aspirin insensitivity. At the conclusion of this research program we will have identified and confirmed a key metabolic and signaling component that transduces acute and chronic hyperglycemia into enhanced platelet activity. The results of these studies may support proceeding with clinical trials to determine what combination of antiplatelet agents would be most beneficial to protect against cardiovascular disease in diabetic patients.
Platelet hyperactivity in diabetic patients plays an important role in the development of cardiovascular disease. We will now explore the glucose specific mechanisms for this increase in thrombosis, by complementing human, mouse and tissue culture cell systems. Our proposed biochemical, genetic and signaling studies may assist in the development of new antiplatelet drugs for diabetic patients, in combating cardiovascular disease.
|Keramati, Ali R; Fathzadeh, Mohsen; Go, Gwang-Woong et al. (2014) A form of the metabolic syndrome associated with mutations in DYRK1B. N Engl J Med 370:1909-19|
|Chakraborty, Raja; Bhullar, Rajinder P; Dakshinamurti, Shyamala et al. (2014) Inverse agonism of SQ 29,548 and Ramatroban on Thromboxane A2 receptor. PLoS One 9:e85937|
|Obinata, Hideru; Gutkind, Sarah; Stitham, Jeremiah et al. (2014) Individual variation of human S1P? coding sequence leads to heterogeneity in receptor function and drug interactions. J Lipid Res 55:2665-75|
|Tang, Wai Ho; Stitham, Jeremiah; Jin, Yu et al. (2014) Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. Circulation 129:1598-609|
|Stitham, J; Vanichakarn, P; Ying, L et al. (2014) Cardiovascular pharmacogenetics of anti-thrombotic agents and non-steroidal anti-inflammatory drugs. Curr Mol Med 14:909-31|
|Vanichakarn, P; Hwa, J; Stitham, J (2014) Cardiovascular pharmacogenetics of antihypertensive and lipid- lowering therapies. Curr Mol Med 14:849-79|
|Moore, Jason H; Hwa, John (2014) Editorial: pharmacogenetics and molecular medicine: "so close and yet so far". Curr Mol Med 14:803-4|
|Liu, Renjing; Jin, Yu; Tang, Waiho et al. (2014) Response to letter regarding article, "ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity". Circulation 130:e72|
|Gleim, Scott; Stitham, Jeremiah; Tang, Wai Ho et al. (2013) Human thromboxane A2 receptor genetic variants: in silico, in vitro and "in platelet" analysis. PLoS One 8:e67314|
|Liu, Renjing; Jin, Yu; Tang, Wai Ho et al. (2013) Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation 128:2047-57|
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