The cardioprotective role of sivelestat, a neutrophil elastase inhibitor, has already been demonstrated, but the underlying molecular mechanism remains unclear. This study aimed to explore the mechanism underlying the role of sivelestat in sepsis-induced myocardial dysfunction (SIMD). We found that sivelestat treatment remarkably improved the viability and suppressed the apoptosis of lipopolysaccharide (LPS)-stimulated H9c2 cells. In vivo, sivelestat treatment was associated with an improved survival rate; reduced serum cTnT, TNF-α, IL-1β levels and myocardial TNF-α and IL-1β levels; ameliorated cardiac function and structure; and reduced cardiomyocyte apoptosis. Moreover, sivelestat treatment substantially increased Bcl-2 expression and suppressed caspase-3 and Bax expression in LPS-induced H9c2 cells and in the heart tissues of septic rats. Furthermore, the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathway was activated both in vitro and in vivo. The protective effect of sivelestat against SIMD was reversed by the PI3K inhibitor LY294002. In summary, sivelestat can protect against SIMD by activating the PI3K/AKT/mTOR signaling pathway.

西维来司他（一种中性粒细胞弹性蛋白酶抑制剂）的心脏保护作用已得到证实，但其潜在的分子机制仍不清楚。本研究旨在探讨西维来司他在脓毒症引起的心肌功能障碍（SIMD）中的作用机制。我们发现西维来司他治疗显着提高了脂多糖（LPS）刺激的 H9c2 细胞的活力并抑制了细胞凋亡。在体内，西维来司他治疗与生存率的提高相关；降低血清cTnT、TNF-α、IL-1β水平以及心肌TNF-α和IL-1β水平；改善心脏功能和结构；并减少心肌细胞凋亡。此外，西维来司他治疗显着增加了LPS诱导的H9c2细胞和脓毒症大鼠心脏组织中Bcl-2的表达并抑制了caspase-3和Bax的表达。此外，磷脂酰肌醇3-激酶/蛋白激酶B/雷帕霉素机械靶点(PI3K/AKT/mTOR)信号通路在体外和体内均被激活。西维来司他对 SIMD 的保护作用被 PI3K 抑制剂 LY294002 逆转。总之，西维来司他可以通过激活 PI3K/AKT/mTOR 信号通路来预防 SIMD。