Department of Emergency, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, Jiangsu Province, China.
Department of Intensive Care Unit, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, Jiangsu Province, China.
Inflammation. 2023 Aug;46(4):1133-1143. doi: 10.1007/s10753-023-01804-7. Epub 2023 Apr 13.
Circadian disruption is involved in the progress of sepsis-induced cardiomyopathy (SICM), one of the leading causes of death in sepsis. The molecular mechanism remains ambiguous. In this study, LPS was used to build SICM model in H9c2 cell. The results suggested that LPS induced cytotoxicity via increasing ferroptosis over the time of course. After screening the expressions of six circadian genes, the circadian swing of Bmal1 was dramatically restrained by LPS in H9c2 cell of SIMC vitro model. PcDNA and siRNA were used to upregulate and downregulate Bmal1 and confirmed that Bmal1 inhibited LPS-triggered ferroptosis in H9c2 cells. Then, the results suggested that AKT/p53 pathway was restrained by LPS in H9c2 cell. Rescue test indicated that Bmal1 inhibited LPS-triggered ferroptosis via AKT/p53 pathway in H9c2 cells. In summary, our findings demonstrated that LPS induced cytotoxicity via increasing ferroptosis over the time of course in H9c2 cells and Bmal1 inhibited this toxicity of LPS via AKT/p53 pathway. Although further studies are needed, our findings may contribute to a new insight to mechanism of SICM.
昼夜节律紊乱与脓毒症相关性心肌病（SICM）的进展有关，后者是脓毒症患者死亡的主要原因之一。但其中的分子机制尚不清楚。在本研究中，采用 LPS 构建 SICM 模型的 H9c2 细胞。结果表明，LPS 随时间推移诱导细胞毒性，增加铁死亡。筛选 6 个昼夜节律基因的表达后，发现 LPS 在 SICM 体外模型的 H9c2 细胞中显著抑制 Bmal1 的昼夜节律波动。PcDNA 和 siRNA 用于上调和下调 Bmal1，并证实 Bmal1 抑制 LPS 诱导的 H9c2 细胞铁死亡。然后，结果表明 LPS 在 H9c2 细胞中抑制 AKT/p53 通路。挽救试验表明，Bmal1 通过 AKT/p53 通路抑制 LPS 诱导的 H9c2 细胞铁死亡。总之，我们的研究结果表明 LPS 在 H9c2 细胞中随时间推移诱导细胞毒性，增加铁死亡，Bmal1 通过 AKT/p53 通路抑制 LPS 的这种毒性。尽管还需要进一步的研究，但我们的发现可能为 SICM 的发病机制提供新的见解。
