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A Uniform Shear Assay for Human Platelet and Cell Surface Receptors via Cone-plate Viscometry
Published on: June 5, 2019
Double-stranded DNA enhances platelet activation, thrombosis, and myocardial injury via cyclic GMP-AMP synthase
Wei Zhang1, Yan Zhang1, Liping Han2
1NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 130 Dong'an Road, Shanghai 200032, China.
Aims:
Elevated dsDNA levels in ST-elevated myocardial infarction (STEMI) patients are associated with increased infarct size and worse clinical outcomes. However, the direct effect of dsDNA on platelet activation remains unclear. This study aims to investigate the direct influence of dsDNA on platelet activation, thrombosis, and the underlying mechanisms.
Methods And Results:
Analysis of clinical samples revealed elevated plasma dsDNA levels in STEMI patients, which positively correlated with platelet aggregation and markers of neutrophil extracellular traps such as MPO-DNA and CitH3. Platelet assays demonstrated the activation of the cGAS-STING pathway in platelets from STEMI patients. DsDNA directly potentiated platelet activation and thrombus formation. Mechanistic studies using G150 (cGAS inhibitor), H151 (STING inhibitor), and MCC950 (NLRP3 inhibitor), as well as cGAS-/-, STING-/-, and NLRP3-/- mice, showed that dsDNA activated cGAS, a previously unreported DNA sensor in platelets, and induced activation of the STING/NLRP3/caspase-1/IL-1β axis. This cascade enhanced platelet activation and thrombus formation. Platelet cGAS depletion or Palbociclib, a cGAS-STING inhibitor, approved by the FDA for advanced breast cancer, ameliorated myocardial ischaemia-reperfusion injury in ApoE-/- mice fed with a high-fat diet for 12 weeks.
Conclusions:
These results suggested that dsDNA is a novel driver of platelet activation and thrombus formation in STEMI patients.
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