Cardiovascular research · 2025
Double-stranded DNA enhances platelet activation, thrombosis, and myocardial injury via cyclic GMP-AMP synthase.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Wei, Zhang Yan, Han Liping, Bo Tao, Qi Zhiyong, Zhong Haoxuan, Xu Huajie, Hu Liang, Chen She, Zhang Si
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsNucleotidyltransferasesNLR Family, Pyrin Domain-Containing 3 ProteinHumansPlatelet ActivationBlood PlateletsDNAMembrane ProteinsSignal TransductionST Elevation Myocardial InfarctionMaleMice, KnockoutMice, Inbred C57BLFemaleDisease Models, AnimalInflammasomesThrombosisMiddle AgedMyocardial Reperfusion InjuryMiceCaspase 1Case-Control StudiesAgedExtracellular TrapsFuransIndenesSulfonamidesCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseSTING Protein