International immunopharmacology · 2026
Beyond anticoagulation: Rivaroxaban attenuates acute myocardial inflammatory injury through the PAR2-mROS-TXNIP-NLRP3 pyroptosis axis.
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Zhang Qian, Chen Weiwei, Tsagaankhuu Maralmaa, Xu Yuanzhen, Zheng Haikuo, Zhang Zhongfan, Zhang Wenqi
Аннотация
BACKGROUND: Excessive inflammation and oxidative stress are major drivers of myocardial injury following acute myocardial infarction (MI). NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-driven pyroptosis is the central underlying mechanism of the inflammatory response. In parallel, factor Xa (FXa) activates protease-activated receptor 2 (PAR2), thereby linking coagulation to inflammatory signaling, beyond just hemostasis. Based on this framework, we investigated whether the FXa inhibitor rivaroxaban attenuates acute myocardial inflammatory injury by suppressing PAR2-mediated pyroptosis.
METHODS: A rat MI model was established by permanent ligation of the left anterior descending (LAD) artery. Rivaroxaban was administered for 30 min before LAD ligation and continued thereafter. Cardiac function, myocardial injury, inflammation, oxidative stress, and pyroptosis-related signaling were evaluated using echocardiography, histology, immunostaining, transmission electron microscopy, enzyme-linked immunosorbent assay (ELISA), western blotting, and co-immunoprecipitation. Mechanistic studies were performed in hypoxic neonatal rat cardiomyocytes with PAR2 overexpression, knockdown, and mitochondrial reactive oxygen species (mROS) inhibition.
RESULTS: Rivaroxaban improved cardiac function, attenuated gross/histological myocardial injury, and suppressed oxidative stress and inflammatory responses. Mechanistically, rivaroxaban inhibited NLRP3 inflammasome activation and pyroptosis, evidenced by reduced cleavage of caspase-1 and gasdermin D, and decreased interleukin (IL)-1β/IL-18 production. Rivaroxaban downregulated thioredoxin-interacting protein (TXNIP) and disrupted TXNIP-NLRP3 complex formation. We further identify PAR2, rather than PAR1, as the dominant mediator of FXa-induced pyroptotic signaling. Moreover, rivaroxaban reduced PAR2-dependent mROS generation, while mROS scavenging attenuated PAR2-driven TXNIP/NLRP3 activation. PAR2 overexpression diminished the protective effects of rivaroxaban.
CONCLUSIONS: Rivaroxaban alleviates myocardial injury by inhibiting PAR2-mediated mROS production and downstream TXNIP/NLRP3 inflammasome activation, thereby suppressing pyroptosis. These findings reveal a novel mechanism beyond anticoagulation underlying its cardioprotective effects.
METHODS: A rat MI model was established by permanent ligation of the left anterior descending (LAD) artery. Rivaroxaban was administered for 30 min before LAD ligation and continued thereafter. Cardiac function, myocardial injury, inflammation, oxidative stress, and pyroptosis-related signaling were evaluated using echocardiography, histology, immunostaining, transmission electron microscopy, enzyme-linked immunosorbent assay (ELISA), western blotting, and co-immunoprecipitation. Mechanistic studies were performed in hypoxic neonatal rat cardiomyocytes with PAR2 overexpression, knockdown, and mitochondrial reactive oxygen species (mROS) inhibition.
RESULTS: Rivaroxaban improved cardiac function, attenuated gross/histological myocardial injury, and suppressed oxidative stress and inflammatory responses. Mechanistically, rivaroxaban inhibited NLRP3 inflammasome activation and pyroptosis, evidenced by reduced cleavage of caspase-1 and gasdermin D, and decreased interleukin (IL)-1β/IL-18 production. Rivaroxaban downregulated thioredoxin-interacting protein (TXNIP) and disrupted TXNIP-NLRP3 complex formation. We further identify PAR2, rather than PAR1, as the dominant mediator of FXa-induced pyroptotic signaling. Moreover, rivaroxaban reduced PAR2-dependent mROS generation, while mROS scavenging attenuated PAR2-driven TXNIP/NLRP3 activation. PAR2 overexpression diminished the protective effects of rivaroxaban.
CONCLUSIONS: Rivaroxaban alleviates myocardial injury by inhibiting PAR2-mediated mROS production and downstream TXNIP/NLRP3 inflammasome activation, thereby suppressing pyroptosis. These findings reveal a novel mechanism beyond anticoagulation underlying its cardioprotective effects.