Department of Critical Care Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, PR China.
Department of Cardiovascular Surgery, General Hospital of Northern Theater Command of China Medical University, Laboratory of Rescue Center of Severe Wound and Trauma PLA, Shenyang 110016, Liaoning, PR China.
Aging (Albany NY). 2023 Aug 9;15(15):7794-7810. doi: 10.18632/aging.204944.
The respiratory and cardiovascular systems are often the most severely impacted by the rapid onset of sepsis, which can lead to multiple organ failure. The mortality has ranged from 10 to 40% when it has evolved into septic shock. This study sought to demonstrate the potential and role of Hmgcs2 in safeguarding against cardiovascular harm in septic mouse models. The cecal ligament and puncture (CLP) model was used to induce sepsis in C57BL/6 mice, with Hmgcs2 expression in the myocardium of the mice being heightened and inflammatory factors being augmented. Subsequently, we utilized ASOs to silence the hmgcs2 gene, and found that silencing accelerated septic myocardial injury and cardiac dysfunction in CLP mice models. In contrast, hmgcs2 attenuated inflammation and apoptosis and protected against septic cardiomyopathy in murine septicemia models. Src production, spurred on by Hmgcs2, triggered the PI3K/Akt pathway and augmented M2 macrophage polarization. Moreover, the inhibition of M2 polarization by an Src antagonist significantly contributed to apoptosis of cardiomyocytes. Our research revealed that Hmgcs2 inhibited the activation of pro-inflammatory macrophages and, through Src-dependent activation of PI3K/Akt pathway, promoted the anti-inflammatory phenotype, thus safeguarding myocardial damage from sepsis. This offers a novel theoretical basis for prevention and treatment of infectious complications.
呼吸系统和心血管系统通常是脓毒症迅速发作时受影响最严重的系统，这可能导致多器官衰竭。当发展为感染性休克时，死亡率在 10%到 40%之间。本研究旨在证明 Hmgcs2 在保护脓毒症小鼠模型免受心血管损伤方面的潜力和作用。我们使用盲肠结扎和穿刺（CLP）模型在 C57BL/6 小鼠中诱导脓毒症，提高了小鼠心肌中的 Hmgcs2 表达，并增强了炎症因子。随后，我们利用 ASO 沉默 hmgcs2 基因，发现沉默加速了 CLP 小鼠模型中的脓毒性心肌损伤和心功能障碍。相比之下，hmgcs2 减轻了炎症和细胞凋亡，并在小鼠败血症模型中保护了脓毒性心肌病。Hmgcs2 刺激产生的 Src 触发了 PI3K/Akt 通路，并增强了 M2 巨噬细胞极化。此外，Src 拮抗剂对 M2 极化的抑制显著促进了心肌细胞的凋亡。我们的研究表明，Hmgcs2 抑制了促炎巨噬细胞的激活，并通过 Src 依赖性激活 PI3K/Akt 通路，促进了抗炎表型，从而保护心肌免受脓毒症的损伤。这为预防和治疗感染性并发症提供了新的理论基础。
