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Double-stranded DNA enhances platelet activation, thrombosis, and myocardial injury via cyclic GMP-AMP synthase.
Zhang, Wei; Zhang, Yan; Han, Liping; Bo, Tao; Qi, Zhiyong; Zhong, Haoxuan; Xu, Huajie; Hu, Liang; Chen, She; Zhang, Si.
Afiliação
  • Zhang W; NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • Zhang Y; NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • Han L; Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, China.
  • Bo T; NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • Qi Z; Department of Cardiology, National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
  • Zhong H; Department of Cardiology, National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
  • Xu H; Department of Cardiology, National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
  • Hu L; Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • Chen S; NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • Zhang S; NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Cardiovasc Res ; 2024 Sep 20.
Article em En | MEDLINE | ID: mdl-39302147
ABSTRACT

AIMS:

Elevated dsDNA levels in 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 (NETs) 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-1ß 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 ischemia-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. TRANSLATIONAL PERSPECTIVE ST-elevated myocardial infarction (STEMI) patients exhibit high levels of plasma double-stranded DNA (dsDNA), which directly potentiates platelet activation through the platelet cGAS/STING/NLRP3/caspase-1/IL-1ß signaling pathway. STEMI patients may benefit from cGAS inhibition in the prevention of platelet hyperactivity and thrombus formation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Cardiovasc Res Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Cardiovasc Res Ano de publicação: 2024 Tipo de documento: Article