Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, PR China; Department of Pathology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China.
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, PR China; Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Changsha, Hunan Province, PR China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan Province, PR China.
Cytokine. 2024 Oct;182:156733. doi: 10.1016/j.cyto.2024.156733. Epub 2024 Aug 10.
Septic cardiomyopathy is a component of multiple organ dysfunction in sepsis. Mitochondrial dysfunction plays an important role in septic cardiomyopathy. Studies have shown that cyclooxygenase-2 (COX-2) had a protective effect on the heart, and prostaglandin E (PGE), the downstream product of COX-2, was increasingly recognized to have a protective effect on mitochondrial function.
This study aims to demonstrate that COX-2/PGE can protect against septic cardiomyopathy by regulating mitochondrial function.
Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and RAW264.7 macrophages and H9C2 cells were used to simulate sepsis in vitro. The NS-398 and celecoxib were used to inhibit the activity of COX-2. ZLN005 and SR18292 were used to activate or inhibit the PGC-1α activity. The mitochondrial biogenesis was examined through the Mitotracker Red probe, mtDNA copy number, and ATP content detection.
The experimental data suggested that COX-2 inhibition attenuated PGC-1α expression thus decreasing mitochondrial biogenesis, whereas increased PGE could promote mitochondrial biogenesis by activating PGC-1α. The results also showed that the effect of COX-2/PGE on PGC-1α was mediated by the activation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Finally, the effect of COX-2/PGE on the heart was also verified in the septic mice.
Collectively, these results suggested that COX-2/PGE pathway played a cardioprotective role in septic cardiomyopathy through improving mitochondrial biogenesis, which has changed the previous understanding that COX-2/PGE only acted as an inflammatory factor.
脓毒症性心肌病是脓毒症多器官功能障碍的一个组成部分。线粒体功能障碍在脓毒症性心肌病中起着重要作用。研究表明，环氧化酶-2（COX-2）对心脏具有保护作用，COX-2 的下游产物前列腺素 E（PGE）越来越被认为对线粒体功能具有保护作用。
本研究旨在证明 COX-2/PGE 通过调节线粒体功能来预防脓毒性心肌病。
使用盲肠结扎和穿孔（CLP）建立脓毒症小鼠模型，并使用 RAW264.7 巨噬细胞和 H9C2 细胞模拟体外脓毒症。使用 NS-398 和塞来昔布抑制 COX-2 的活性。使用 ZLN005 和 SR18292 激活或抑制 PGC-1α 的活性。通过 Mitotracker Red 探针、mtDNA 拷贝数和 ATP 含量检测来检测线粒体生物发生。
实验数据表明，COX-2 抑制减弱了 PGC-1α 的表达，从而减少了线粒体生物发生，而增加的 PGE 通过激活 PGC-1α 可促进线粒体生物发生。结果还表明，COX-2/PGE 对 PGC-1α 的作用是通过激活环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）介导的。最后，还在脓毒症小鼠中验证了 COX-2/PGE 对心脏的作用。
综上所述，这些结果表明，COX-2/PGE 通路通过改善线粒体生物发生在脓毒性心肌病中发挥心脏保护作用，这改变了以前认为 COX-2/PGE 仅作为炎症因子的观点。
