Ying-Hao Pei, Yu-Shan Yang, Song-Yi Cheng, Hua Jiang, Peng Yu, Xiao-Hu Chen
Department of Intensive Care Unit, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province, Nanjing, China.
Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province, Nanjing, China.
Heliyon. 2024 Aug 31;10(17):e37088. doi: 10.1016/j.heliyon.2024.e37088. eCollection 2024 Sep 15.
One of the most prevalent causes of death in sepsis is sepsis-induced cardiomyopathy (SICM). Circadian disruption is involved in the progress of sepsis. However, the molecular mechanism remains unclear.
Here, we built LPS-induced SICM and models. LPS was administrated at the particular Zeitgeber times (ZT), ZT4-ZT10-ZT16-ZT22 and ZT10-ZT22 in and experiments, respectively.
In experiment, injection of LPS at ZT10 induced higher infiltration of inflammatory cells and content of intracellular Fe, and lower level of Glutathione peroxidase 4 (GPX4) and cardiac function than other ZTs (P < 0.05), which indicated that myocardial ferroptosis in septic rat presented a time of day-dependent manner. Bmal-1 protein and mRNA levels of injection of LPS at ZT10 were lower than those at other three ZTs (P < 0.05). The ratios of pAKT/AKT at ZT4 and ZT10 LPS injection were lower than those at ZT16 and ZT22 (P < 0.05). Nrf2 protein levels at ZT10 LPS injection were lower than those at other three ZTs (P < 0.05). These results indicated that the circadian of Bmal-1 and its downstream AKT/Nrf2 pathway in rat heart were inhibited under SICM condition. Consistent with experiment, we found LPS could significantly reduce the expressions of Bmal-1 protein and mRNA in H9c2 cell. Up-regulation of Bmal-1 could reduce the cell death, oxidative stress, ferroptosis and activation of AKT/Nrf2 pathway at both ZT10 and ZT22 LPS administration. Conversely, its down-regulation presented opposite effects. AKT siRNA could weaken the effect of Bmal-1 pcDNA.
Ferroptosis presented the time of day-dependent manners via Bmal-1/AKT/Nrf2 in and models of SICM.
脓毒症诱导的心肌病（SICM）是脓毒症最常见的死亡原因之一。昼夜节律紊乱参与脓毒症的进展。然而，其分子机制仍不清楚。
在此，我们构建了脂多糖（LPS）诱导的SICM模型。在实验1和实验2中，分别在特定的授时时间（ZT），即ZT4-ZT10-ZT16-ZT22和ZT10-ZT22给予LPS。
在实验1中，与其他ZT时间相比，在ZT10注射LPS诱导更高的炎性细胞浸润和细胞内铁含量，以及更低水平的谷胱甘肽过氧化物酶4（GPX4）和心脏功能（P<0.05），这表明脓毒症大鼠的心肌铁死亡呈现出昼夜依赖性。在ZT10注射LPS时，Bmal-1蛋白和mRNA水平低于其他三个ZT时间（P<0.05）。在ZT4和ZT10注射LPS时，pAKT/AKT的比值低于ZT16和ZT22时（P<0.05）。在ZT10注射LPS时，Nrf2蛋白水平低于其他三个ZT时间（P<0.05）。这些结果表明，在SICM条件下，大鼠心脏中Bmal-1及其下游AKT/Nrf2通路的昼夜节律受到抑制。与实验1一致，我们发现LPS可显著降低H9c2细胞中Bmal-1蛋白和mRNA的表达。上调Bmal-1可在ZT10和ZT22给予LPS时减少细胞死亡、氧化应激、铁死亡并激活AKT/Nrf2通路。相反，其下调则呈现相反的效果。AKT小干扰RNA可削弱Bmal-1质粒的作用。
在SICM的实验1和实验2模型中，铁死亡通过Bmal-1/AKT/Nrf2呈现出昼夜依赖性方式。
