BRD4 inhibition by JQ1 protects against LPS-Induced Cardiac Dysfunction by inhibiting SIRT1-dependent activation of NLRP3 inflammasomes

Abstract JQ1, a BRD4 protein inhibitor, first identified because of its therapeutic role in cancer, has gradually demonstrated a protective effect on the heart in recent years; however, it is unclear whether JQ1 also plays a role in LPS-induced cardiac dysfunction. This paper aims to investigate the effects of the BRD4 inhibitor JQ1 on LPS-induced cardiac dysfunction and its mechanism. In the experiments, we found that BRD4 was significantly upregulated in the hearts of LPS-treated mice.JQ1 treatment improved survival and cardiac function in LPS-treated mice and reduced cardiomyopathologic injury, inflammation, and oxidative injury.JQ1 treatment similarly reduced the release of lactate dehydrogenase and inflammatory factors in H9C2 cells treated with LPS.JQ1 significantly upregulated silent information regulator 1 (SIRT1) expression and suppressed the upregulation of NOD-like receptor protein 3 (NLRP3), cleaved caspase-1, and GSDMD in heart tissues induced by LPS.Meanwhile, we obtained the same results in H9C2 cells treated with LPS. The administration of the SIRT1 inhibitor (EX527) intervention partially blocked the JQ1-mediated downregulation of NLRP3, cleaved caspase-1, GSDMD in LPS-induced H9C2 cells. Therefore, we propose that JQ1 can improve LPS-induced cardiac dysfunction by inhibiting SIRT1-dependent activation of NLRP3 inflammasomes, which may be a promising strategy for treating sepsis cardiomyopathy.