Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China; Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Hangzhou 310009, China; Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China.
Department of Dermatology, Air Force Medical Center, PLA, Beijing, 100142, China.
Biomed Pharmacother. 2024 Nov;180:117455. doi: 10.1016/j.biopha.2024.117455. Epub 2024 Sep 27.
This study aims to evaluate the therapeutic effects of sodium octanoate (SO), a medium-chain fatty acid salt, on SIMD in a murine model and to explore its underlying mechanisms.
Male mice were subjected to sepsis models through two methods: intraperitoneal injection of lipopolysaccharide (LPS) and cecal ligation and punction (CLP). Mice received interval doses of SO every 2 hours or 4 hours for a total of six times or three times after LPS treatment. The relationship between SO and G protein-coupled receptor 84 (GPR84) was evaluated through GEO data analysis and molecular docking studies. DBA/2 mice were used to study the role of the GPR84 protein in the SO-mediated protection. Energy metabolomics was utilized to comprehensively assess the impact of SO on the levels of cardiac energy metabolic products in septic mice. histone modification identification techniques were used to further identify the specific sites of histone modification in the hearts of SO-treated septic mice.
SO treatment significantly improved myocardial contractile function, restored the oxidative stress imbalance and enhanced the myocardium's resistance to oxidative injury. SO significantly promotes the expression of GPR84. The loss of GPR84 function markedly attenuates the protective effects of SO. SO enhanced myocardial energy metabolism by promoting the synthesis of acetyl-CoA and upregulating genes involved in fatty acid β-oxidation which were abolished by medium-chain acyl-CoA dehydrogenase (MCAD) knockdown. SO induced histone acetylation, particularly at H3K123 and H3K80.
Our study demonstrates that SO exerts protective effects against SIMD through both GPR84-mediated anti-inflammatory and antioxidant actions and GPR84-independent enhancement of myocardial energy metabolism, possibly mediated by MCAD.
本研究旨在评估中链脂肪酸盐辛酸钠（SO）在小鼠模型中对 SIMD 的治疗效果，并探讨其潜在机制。
雄性小鼠通过两种方法建立脓毒症模型：腹腔注射脂多糖（LPS）和盲肠结扎穿孔（CLP）。LPS 处理后，小鼠每隔 2 小时或 4 小时接受间隔剂量的 SO，共 6 次或 3 次。通过 GEO 数据分析和分子对接研究评估 SO 与 G 蛋白偶联受体 84（GPR84）的关系。使用 DBA/2 小鼠研究 GPR84 蛋白在 SO 介导的保护中的作用。能量代谢组学用于全面评估 SO 对脓毒症小鼠心脏能量代谢产物水平的影响。组蛋白修饰鉴定技术用于进一步鉴定 SO 处理脓毒症小鼠心脏中组蛋白修饰的特定部位。
SO 治疗显著改善心肌收缩功能，恢复氧化应激失衡，增强心肌对氧化损伤的抵抗力。SO 显著促进 GPR84 的表达。GPR84 功能丧失显著减弱 SO 的保护作用。SO 通过促进乙酰辅酶 A 的合成和上调脂肪酸β氧化相关基因的表达来增强心肌能量代谢，这一作用被中链酰基辅酶 A 脱氢酶（MCAD）敲低所阻断。SO 诱导组蛋白乙酰化，特别是在 H3K123 和 H3K80 上。
本研究表明，SO 通过 GPR84 介导的抗炎和抗氧化作用以及 GPR84 非依赖性增强心肌能量代谢发挥对 SIMD 的保护作用，可能通过 MCAD 介导。
