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Aerobic glycolysis fuels platelet activation
While it would not be possible to predict the off-target adverse effects of the small-molecule metabolic modula- tors at this stage, the potential for non-selective effects being beneficial to overall cardiovascular health cannot be overemphasized. DCA has been found to be effective in improving cardiac function after ischemia/reperfusion injury46-48 as well as in preventing restenosis after vessel injury49 in preclinical models. There is substantial clinical evidence linking higher serum DHEA levels to decreased cardiovascular mortality.50 Small-molecule activators of PKM2 have been shown to reverse the pro-inflammatory phenotype of monocytes/macrophages isolated from patients with atherosclerotic coronary artery disease.51
Although DASA is only in preclinical stages of develop- ment as an antineoplastic drug,52 DCA is already under clinical trials against various cancers10,53 and congenital lac- tic acidosis8,54 while DHEA was recently granted Food and Drug Administration approval for clinical use in post- menopausal women.9 Hence, considerable information on the safety and pharmacokinetics of the latter drugs in humans is already available, which could in future pave the way for clinical trials of the drugs as potential anti-
platelet/anti-thrombotic agents in the management of thrombotic disorders. In conclusion, this study suggests an indispensable role for platelet energy metabolism in thrombogenesis with potential implications for the devel- opment of anti-thrombotic strategies. Future investiga- tions directed at metabolic adaptations of platelets within a developing thrombus in vivo could potentially identify many more therapeutic opportunities.
Acknowledgments
This research was supported by a JC Bose fellowship and grants received by D. Dash from the Department of Biotechnology (DBT), Science and Engineering Research Board (SERB) and Department of Science and Technology (DST), Government of India, the Indian Council of Medical Research (ICMR) and the Council of Scientific and Industrial Research (CSIR). A.T. and D.G. are recipients of UGC-JRF and CSIR- JRF, respectively. We are grateful to the technical staff for their assistance in performing the histopathological analysis of murine lung tissue. We thank Pradyumna Kulkarni for proofreading the manuscript. D.D. acknowledges assistance from the Humboldt Foundation, Germany.
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