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

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          Key Points

          • DCA, an inhibitor of PDKs, impedes glucose uptake and aerobic glycolysis in activated platelets.

          • DCA inhibits agonist-induced human and mouse platelet aggregation and arterial thrombosis without altering hemostasis in mice.

          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 FeCl 3-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.

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          Author and article information

          Journal
          Blood Adv
          Blood Adv
          bloodoa
          Blood Adv
          Blood Advances
          Blood Advances
          American Society of Hematology (Washington, DC )
          2473-9529
          2473-9537
          14 August 2018
          14 August 2018
          14 August 2018
          : 2
          : 15
          : 2029-2038
          Affiliations
          [1 ]Department of Internal Medicine and
          [2 ]Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA
          Author information
          http://orcid.org/0000-0001-8554-0898
          Article
          PMC6093723 PMC6093723 6093723 2018/022392
          10.1182/bloodadvances.2018022392
          6093723
          30108111
          c6264384-2656-47e8-8636-9160a2eb0d98
          © 2018 by The American Society of Hematology
          History
          : 13 June 2018
          : 11 July 2018
          Page count
          Pages: 10
          Categories
          29
          Thrombosis and Hemostasis
          Custom metadata
          free

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