Department of Intensive Care Unit, Baoding First Central Hospital, Baoding, China.
Department of General Surgery, Baoding First Central Hospital, Baoding, China.
Int Immunopharmacol. 2024 Feb 15;128:111466. doi: 10.1016/j.intimp.2023.111466. Epub 2024 Jan 4.
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.
西维来司他作为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，但潜在的分子机制尚不清楚。本研究旨在探讨西维来司他在脓毒症诱导的心肌功能障碍（SIMD）中的作用机制。我们发现，西维来司他治疗可显著提高活力并抑制脂多糖（LPS）刺激的 H9c2 细胞凋亡。在体内，西维来司他治疗与提高生存率、降低血清 cTnT、TNF-α、IL-1β水平以及心肌 TNF-α和 IL-1β水平、改善心功能和结构以及减少心肌细胞凋亡有关。此外，西维来司他治疗可显著增加 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 caspase-3 和 Bax 的表达。此外，PI3K/AKT/mTOR 信号通路在体外和体内均被激活。PI3K 抑制剂 LY294002 逆转了西维来司他对 SIMD 的保护作用。总之，西维来司他通过激活 PI3K/AKT/mTOR 信号通路来防止 SIMD。
