Reduced silent information regulator 1 signaling exacerbates sepsis-induced myocardial injury and mitigates the protective effect of a liver X receptor agonist
Reduced silent information regulator 1 signaling exacerbates sepsis-induced myocardial injury and mitigates the protective effect of a liver X receptor agonist
复制标题
沉默信息调节器 1 信号传导减少会加剧脓毒症引起的心肌损伤并减轻肝脏 X 受体激动剂的保护作用
DOI：
10.1016/j.freeradbiomed.2017.10.005
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发表时间：
2017-12-01
影响因子：
7.4
通讯作者：
Cao, Feng
中科院分区：
文献类型：
--
作者：
Han, Dong;Li, Xiang;Cao, Feng
心肌损伤和功能障碍是脓毒症的重要表现。先前的研究报告称，肝脏 X 受体 (LXR) 激活在脓毒症期间具有保护作用。然而，LXR 激活是否可以预防脓毒性心脏损伤及其潜在机制仍不清楚。本研究旨在确定 LXR 激活在脓毒症心脏中的作用，重点关注 SIRT1（沉默信息调节因子 1）信号传导。在存在或不存在 LXR 激动剂 T0901317 的情况下，通过盲肠结扎和穿刺 (CLP) 使雄性心脏特异性 SIRT1 敲除小鼠 (SIRT1-/-) 及其野生型同窝小鼠遭受败血症。在 CLP 后 7 天内记录小鼠的存活率。我们的结果表明，与野生型同窝小鼠相比，SIRT1-/- 小鼠的死亡率和心肌损伤加剧。同时，T0901317 治疗提高了小鼠的存活率，同时野生型小鼠的心肌损伤和功能障碍也得到了显着改善，但 SIRT1-/- 小鼠的心肌损伤和功能障碍却没有显着改善。此外，在野生型小鼠中，T0901317治疗可抑制心肌炎症细胞因子（TNF-α、IL-6、IL-1β、MCP-1、MPO和HMGB1）、氧化应激（ROS生成、MDA）、内质网（ER）应激（CHOP、GRP78、GRP94、IRE1α和ATF6的蛋白水平）以及CLP后心脏细胞凋亡的水平，但在野生型小鼠中则不然。 SIRT1-/- 小鼠。从机制上讲，T0901317增强了SIRT1信号传导以及随后抗氧化FoxO1和抗ER应激HSF1的脱乙酰化和激活，以及促炎性NF-κB和促凋亡P53的脱乙酰化和抑制，从而减轻脓毒症引起的心肌损伤和功能障碍。我们的数据支持 LXR 激活作为缓解心脏脓毒性损伤的有效策略的承诺。
Myocardial injury and dysfunction are critical manifestations of sepsis. Previous studies have reported that liver X receptor (LXR) activation is protective during sepsis. However, whether LXR activation protects against septic heart injury and its underlying mechanisms remain elusive. This study was designed to determine the role of LXR activation in the septic heart with a focus on SIRT1 (silent information regulator 1) signaling. Male cardiac-specific SIRT1 knockout mice (SIRT1-/-) and their wild-type littermates were subjected to sepsis by cecal ligation and puncture (CLP) in the presence or absence of LXR agonist T0901317. The survival rate of mice was recorded during the 7-day period post CLP. Our results demonstrated that SIRT1-/- mice suffered from exacerbated mortality and myocardial injury in comparison with their wild-type littermates. Meanwhile, T0901317 treatment improved mice survival, accompanied by significant ameliorations of myocardial injury and dysfunction in wild-type mice but not in SIRT1-/- mice. Furthermore, the levels of myocardial inflammatory cytokines (TNF-alpha, IL-6, IL-1 beta, MCP-1, MPO and HMGB1), oxidative stress (ROS generation, MDA), endoplasmic-reticulum (ER) stress (protein levels of CHOP, GRP78, GRP94, IRE1 alpha, and ATF6), and cardiac apoptosis following CLP were inhibited by T0901317 treatment in wild-type mice but not in SIRT1-/- mice. Mechanistically, T0901317 enhanced SIRT1 signaling and the subsequent deacetylation and activation of antioxidative FoxO1 and anti-ER stress HSF1, as well as the deacetylation and inhibition of pro-inflammatory NF-kappa B and pro-apoptotic P53, thereby alleviating sepsis-induced myocardial injury and dysfunction. Our data support the promise of LXR activation as an effective strategy for relieving heart septic injury.