Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinases, inhibits platelet aggregation and arterial thrombosis.

Abstract

Resting platelets rely on oxidative phosphorylation (OXPHOS) and aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen) to generate adenosine triphosphate, whereas activated platelets exhibit a high level of aerobic glycolysis, suggesting the existence of metabolic flexibility in platelets. Mitochondrial pyruvate dehydrogenase kinases (PDK 1-4) play a pivotal role in metabolic flexibility by inhibiting pyruvate dehydrogenase complex. We determined whether metabolic reprogramming, diverting metabolism from aerobic glycolysis back to OXPHOS, would inhibit platelet function. PDKs activity in human and mouse platelets was inhibited with dichloroacetic acid (DCA), a potent inhibitor of all 4 forms of PDK. Human and mouse platelets pretreated with DCA exhibited decreased platelet aggregation to suboptimal doses of collagen, convulxin, thrombin, and adenosine diphosphate concomitant with decreased glucose uptake. Bioenergetics profile revealed that platelets pretreated with DCA exhibited decreased aerobic glycolysis in response to convulxin only. Furthermore, DCA inhibited ATP secretion, thromboxane A2 generation, and tyrosine phosphorylation of Syk and PLCγ2 in response to collagen or convulxin in human and mouse platelets (P < .05 vs vehicle treated). In the flow chamber assay, human and mouse blood pretreated with DCA formed smaller thrombi when perfused over collagen for 10 minutes at an arterial shear rate of 1500 s-1 (P < .05 vs control). Wild-type mice pretreated with DCA were less susceptible to thrombosis in the FeCl3-induced carotid and laser injury-induced mesenteric artery thrombosis models (P < .05 vs vehicle control), without altering hemostasis. Targeting metabolic plasticity with DCA may be explored as a novel strategy to inhibit platelet function.

• Authors: Manasa K Nayak, Nirav Dhanesha, Prakash Doddapattar, Omar Rodriguez, Vijay K Sonkar, Sanjana Dayal, Anil K Chauhan
• Journal: Blood advances (Blood Adv) Vol. 2 Issue 15 Pg. 2029-2038 (08 14 2018) ISSN: 2473-9537 [Electronic] United States
• PMID: 30108111 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• Fibrinolytic Agents
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Thromboxane A2
• Dichloroacetic Acid
• Protein Serine-Threonine Kinases
• Phospholipase C gamma

Topics

• Animals
• Blood Platelets (cytology, metabolism)
• Dichloroacetic Acid (pharmacology)
• Female
• Fibrinolytic Agents (pharmacology)
• Humans
• Male
• Mice
• Phospholipase C gamma (metabolism)
• Platelet Aggregation (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Thromboxane A2 (metabolism)