Tubastatin A Improves Post‐Resuscitation Myocardial Dysfunction by Inhibiting NLRP3‐Mediated Pyroptosis Through Enhancing Transcription Factor EB Signaling

Abstract

Background Myocardial dysfunction is the leading cause of early death following successful cardiopulmonary resuscitation (CPR) in people with cardiac arrest (CA), which is potentially driven by cell pyroptosis mediated by NOD‐like receptor pyrin domain 3 (NLRP3) inflammasome. Recently, histone deacetylase 6 (HDAC6) inhibition was shown to exert effective myocardial protection against regional ischemia/reperfusion injury. In this study, we investigated whether tubastatin A, a specific histone deacetylase 6 inhibitor, could improve postresuscitation myocardial dysfunction through the inhibition of NLRP3‐mediated cell pyroptosis and its modulation mechanism. Methods and Results Healthy male white domestic swine were used to establish the model of CA/CPR in vivo, and the H9c2 cardiomyocyte hypoxia/reoxygenation model was used to simulate the CA/CPR process in vitro. Consequently, tubastatin A inhibited NLRP3 inflammasome activation, decreased proinflammatory cytokines production and cell pyroptosis, and increased cell survival after hypoxia/reoxygenation in H9c2 cardiomyocytes in vitro. In addition, tubastatin A increased the acetylated levels of transcription factor EB and its translocation to the nucleus, and its protective effect above was partly abrogated by transcription factor EB short interfering RNA after hypoxia/reoxygenation in H9c2 cardiomyocytes. Similarly, tubastatin A promoted cardiac transcription factor EB nuclear translocation, inhibited NLRP3‐mediated cell pyroptosis, and mitigated myocardial dysfunction after CA/CPR in swine. Conclusions The inhibition of histone deacetylase 6 activity by tubastatin A limited NLRP3 inflammasome activation and cell pyroptosis probably through the enhancement of transcription factor EB signaling, and therefore improved myocardial dysfunction after CA/CPR.

Keywords

• cardiopulmonary resuscitation
• cell pyroptosis
• myocardial dysfunction
• transcription factor EB
• tubastatin A