Telaprevir attenuates caspase-11-dependent pyroptosis in mouse heart following ischemia/reperfusion via inhibition of MALT1/TRAF6 pathway.

Pyroptosis is one of the major forms of cardiomyocyte death following ischemia/reperfusion (I/R). Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)/Tumor necrosis factor receptor associated factor 6 (TRAF6) pathway is involved in cardiomyocyte pyroptosis in mouse heart following I/R, and telaprevir, a hepatitis C virus protease inhibitor, has been predicted as a potential inhibitor of MALT1. This study aims to explore the effect of telaprevir on I/R-induced cardiomyocyte pyroptosis. The C57BL/6J mouse was subjected to 45 min-ischemia plus 24 h-reperfusion to establish the myocardial I/R injury model, while H9c2 cardiomyocytes were exposed to hypoxia for 8 h plus reoxygenation for 24 h (H/R) to simulate the I/R pathological process in vitro. Compared to the control group, pyroptosis was significantly increased in the I/R-treated mouse heart or the H/R-treated cardiomyocytes, evidenced by the elevated GSDMD and caspase-11 cleavage. Compared to the vehicle, telaprevir reduced myocardial infarcted size and cleavage of caspase-11 and gasdermin D (GSDMD) in mouse heart following I/R and cultured cardiomyocytes subjected to H/R in a dose-dependent manner. Mechanistically, telaprevir inhibited the recruitment of TRAF6 by MALT1, concomitant with the reduced recruitment of caspase-11 by TRAF6, and in turn, attenuated caspase-11 K63 poly-ubiquitination and activation, which was further confirmed by knockdown of TRAF6. Based on these results, we concluded that telaprevir could protect mouse heart against I/R injury by reducing caspase-11-dependent pyroptosis through inhibition of MALT1/TRAF6 pathway.