Ticagrelor reduces doxorubicin-induced pyroptosis of rat cardiomyocytes by targeting GSK-3β/caspase-1

Abstract

Doxorubicin (Dox) is a widely used clinical drug whose cardiotoxicity cannot be ignored. Pyroptosis (inflammatory cell death) has gradually gained attention in the context of Dox-induced cardiotoxicity. In addition to the inhibition of platelet activation by ticagrelor, little is known about its other pharmacological effects. Glycogen synthase kinase 3β (GSK-3β) has been shown to contribute to the pathological process of pyroptosis, but whether it is related to the potential role of ticagrelor is unclear. In this study, we investigated the effects of ticagrelor on Dox-induced pyroptosis in cardiomyocytes. Rats were treated with ticagrelor (7.5 mg/kg, i.g.) 1 h before intravenous injection of Dox (2.5 mg/kg), once every 3 days, six times in total. Hearts were collected for histochemical analysis and western blot detection 8 weeks after the last administration. Ticagrelor was shown to significantly improve cardiac function by inhibiting GSK-3β/caspase-1/GSDMD activation. In vitro experiments were conducted using rat cardiac myocytes (RCMs) and rat embryonic cardiac-derived H9c2 cells. Pretreatment with ticagrelor (10 μm) significantly inhibited Dox (1 μm)-induced hypertrophy and reversed the upregulation of GSDMD-NT expression. We showed that ticagrelor suppressed the activation of Akt caused by Dox in the heart tissue as well as in RCMs/H9c2 cells caused by Dox. When GSK-3β expression was absent in H9c2 cells, the inhibitory effect of ticagrelor on Dox-induced caspase-1/GSDMD activation was weakened. These data showed that ticagrelor reduced Dox-induced pyroptosis in rat cardiomyocytes by targeting GSK-3β/caspase-1.

Pyroptosis and inflammation‑mediated endothelial dysfunction may act as key factors in the development of erectile dysfunction (Review)

“…The destruction of the cell membrane associated with the formation of these pores alters intracellular pressure and cell permeability, causing the cell to swell, rupture and lyse. Notably, caspase-1 also cleaves immature IL-1β and IL-18 precursors to form active IL-1β and IL-18, which are released from the cell through the membrane pores to induce cell pyroptosis ( 52 ). Caspase-1-mediated pyroptosis is important in the regulation of ED.…”

Recent Advances in the Mechanisms of Cell Death and Dysfunction in Doxorubicin Cardiotoxicity

“…By reducing the expression of NOX1/2/3, TLR2/4, and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF- B), exogenous 8-hydroxy-deoxyguanosine (8-OHdG) attenuates DOX-induced pyroptosis [ 74 ]. Ticagrelor attenuates DOX-induced pyroptosis of cardiomyocytes by targeting glycogen synthase kinase-3 /caspase-1 [ 75 ]. Nifurazine suppressed DOX-induced pyroptosis by down-regulating the protein expression of TLR4, NF- B, thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1, and the GSDMD-N terminus [ 76 ].…”