Abstract：
Myocardial injury and cardiovascular dysfunction are the most common complications of sepsis, and effective therapeutic candidate is still lacking. This study aims to investigate the protective effect of oxycodone in myocardial injury of lipopolysaccharide-induced sepsis and its related signalling pathways. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout mice, as well as H9c2 cardiomyocytes cultures treated with lipopolysaccharide (LPS) were used as models of septic myocardial injury. H9c2 cardiomyocytes culture showed that oxycodone protected cells from pyroptosis induced by LPS. Mice model confirmed that oxycodone pretreatment significantly attenuated myocardial pathological damage and improved cardiac function demonstrated by increased ejection fraction (EF) and fractional shortening (FS), as well as decreased cardiac troponin I (cTnI) and creatine kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of inflammatory factors and oxidative stress damage induced by LPS, which involves pyroptosis-related proteins including: Nod-like receptor protein 3 (NLRP3), Caspase 1, Apoptosis-associated speck-like protein contain a CARD (ASC), and Gasdermin D (GSDMD). These changes were mediated by Nrf2 and heme oxygenase-1 (HO-1) because Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly reversed the beneficial effect of oxycodone on oxidative stress, inflammatory responses and NLRP3-mediated pyroptosis. Our findings yielded that oxycodone therapy reduces LPS-induced myocardial injury by suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signalling pathway in vivo and in vitro.
摘要：
心肌损伤和心血管功能障碍是脓毒症最常见的并发症,仍然缺乏有效的治疗候选物。本研究旨在探讨羟考酮对内毒素诱导脓毒症心肌损伤的保护作用及其相关信号通路。野生型和核因子红系2相关因子2（Nrf2）敲除小鼠，以及用脂多糖（LPS）处理的H9c2心肌细胞培养物用作脓毒症心肌损伤的模型。H9c2心肌细胞培养显示羟考酮保护细胞免受LPS诱导的焦亡。小鼠模型证实，羟考酮预处理可显着减轻心肌病理损伤，改善心脏功能，表现为增加射血分数（EF）和缩短分数（FS）。以及降低的心肌肌钙蛋白I（cTnI）和肌酸激酶同工酶MB（CK-MB）。羟考酮还能降低LPS诱导的炎症因子水平和氧化应激损伤,涉及与焦亡相关的蛋白质，包括：Nod样受体蛋白3（NLRP3），半胱天冬酶1，凋亡相关斑点样蛋白含有CARD（ASC），和GasderminD（GSDMD）。这些变化是由Nrf2和血红素加氧酶-1（HO-1）介导的，因为Nrf2敲除小鼠或H9c2细胞中的Nrf2敲除显著逆转羟考酮对氧化应激的有益作用，炎症反应和NLRP3介导的焦亡。我们的发现表明，羟考酮治疗可通过体内和体外Nrf2/HO-1信号通路抑制NLRP3介导的焦亡，从而减少LPS诱导的心肌损伤。
