Journal article
Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinases, inhibits platelet aggregation and arterial thrombosis
Blood advances, Vol.2(15), pp.2029-2038
08/14/2018
DOI: 10.1182/bloodadvances.2018022392
PMCID: PMC6093723
PMID: 30108111
Abstract
DCA, an inhibitor of PDKs, impedes glucose uptake and aerobic glycolysis in activated platelets.\nDCA inhibits agonist-induced human and mouse platelet aggregation and arterial thrombosis without altering hemostasis in mice.\nResting 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 (\nP\n< .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\n−1\n(\nP\n< .05 vs control). Wild-type mice pretreated with DCA were less susceptible to thrombosis in the FeCl\n3\n-induced carotid and laser injury–induced mesenteric artery thrombosis models (\nP\n< .05 vs vehicle control), without altering hemostasis. Targeting metabolic plasticity with DCA may be explored as a novel strategy to inhibit platelet function.
Details
- Title: Subtitle
- Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinases, inhibits platelet aggregation and arterial thrombosis
- Creators
- Manasa K Nayak - Department of Internal Medicine andNirav Dhanesha - Department of Internal Medicine andPrakash Doddapattar - Department of Internal Medicine andOmar Rodriguez - Stead Family Department of Pediatrics, University of Iowa, Iowa City, IAVijay K Sonkar - Department of Internal Medicine andSanjana Dayal - Department of Internal Medicine andAnil K Chauhan - Department of Internal Medicine and
- Resource Type
- Journal article
- Publication Details
- Blood advances, Vol.2(15), pp.2029-2038
- DOI
- 10.1182/bloodadvances.2018022392
- PMID
- 30108111
- PMCID
- PMC6093723
- NLM abbreviation
- Blood Adv
- ISSN
- 2473-9529
- eISSN
- 2473-9537
- Publisher
- American Society of Hematology; Washington, DC
- Language
- English
- Date published
- 08/14/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984070380502771
Metrics
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