Department of Anesthesiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Department of Hematology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113461. doi: 10.1016/j.intimp.2024.113461. Epub 2024 Oct 23.
Sepsis, a systemic inflammatory condition, is a leading cause of mortality due to cardiovascular injury. Sepsis and cellular senescence are closely related, yet the specific mechanisms are still unclear. This study aims to identify a novel therapeutic target for mitigating sepsis-induced myocardial injury.
We initially assessed serum inflammatory markers and myocardial injury indicators in septic mice. This involved observing inflammatory cell infiltration in ventricular muscle tissue, assessing cardiac function, and recording electrocardiograms. We examined the expression of connexin 40 (Cx40) and connexin 43 (Cx43) and analyzed mitochondrial structures in ventricular tissues. A conditional heart-specific Nppb knockout mouse model was then developed in mice to evaluate these changes. Ventricular tissues were analyzed via mRNA sequencing to identify differentially expressed genes (DEGs), which were cross-referenced with senescence-related genes to identify key hub genes. The expression and distribution of hub genes were subsequently analyzed by single-cell analysis. Finally, the expression of the senescence-related gene CCL2, along with cardiac structure and function, was validated in a conditional heart-specific Nppb knockout sepsis mouse model.
Myocardial injury severity positively correlated with serum brain natriuretic peptide (BNP) in septic mice. Conditional heart-specific Nppb knockout improved myocardial injury outcomes in mice with sepsis. The DEGs identified in the conditional heart-specific Nppb knockout model overlapped with senescence-related genes, identifying seven upregulated genes associated with inflammation, cardiac contraction and apoptotic pathways. Single-cell analysis confirmed high CCL2 levels and an increased macrophage presence correlating with sepsis progression. Conditional heart-specific Nppb knockout reduced CCL2 levels, which were associated with improved cardiac structure and function.
This study confirms that conditional heart-specific Nppb knockout reduces CCL2 expression, thereby ameliorating myocardial injury in septic mice. Targeting Nppb to regulate the senescence-related gene CCL2 may represent an effective strategy for treating myocardial injury in septic patients.
败血症是一种全身性炎症状态，是心血管损伤导致死亡的主要原因。败血症和细胞衰老密切相关，但具体机制尚不清楚。本研究旨在寻找一种减轻败血症引起的心肌损伤的新治疗靶点。
我们首先评估了败血症小鼠的血清炎症标志物和心肌损伤标志物。观察心室肌组织中炎症细胞浸润，评估心功能，记录心电图。我们检测了连接蛋白 40（Cx40）和连接蛋白 43（Cx43）的表达，并分析了心室组织中的线粒体结构。然后在小鼠中建立了条件性心脏特异性 Nppb 敲除小鼠模型，以评估这些变化。通过 mRNA 测序分析心室组织，以鉴定差异表达基因（DEGs），并与衰老相关基因进行交叉参考，以鉴定关键枢纽基因。然后通过单细胞分析分析枢纽基因的表达和分布。最后，在条件性心脏特异性 Nppb 敲除败血症小鼠模型中验证了衰老相关基因 CCL2 的表达以及心脏结构和功能。
败血症小鼠的心肌损伤严重程度与血清脑钠肽（BNP）呈正相关。条件性心脏特异性 Nppb 敲除可改善败血症小鼠的心肌损伤结局。在条件性心脏特异性 Nppb 敲除模型中鉴定的 DEGs 与衰老相关基因重叠，鉴定出与炎症、心脏收缩和凋亡途径相关的七个上调基因。单细胞分析证实，随着败血症的进展，CCL2 水平升高且巨噬细胞增多。条件性心脏特异性 Nppb 敲除降低了 CCL2 水平，从而改善了心脏结构和功能。
本研究证实，条件性心脏特异性 Nppb 敲除可降低败血症小鼠的 CCL2 表达，从而改善其心肌损伤。靶向 Nppb 调节衰老相关基因 CCL2 可能是治疗败血症患者心肌损伤的有效策略。
