Chen Jie, Zhang Wei-Jian, Liu Xiao-Yu, Hu Tian-Peng, Gao Nan, Li Zhong-Hao, Wang Yu, Zhang Guo-Qiang
Department of Emergency, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100029, China.
Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, China.
Inflammation. 2025 Jan 22. doi: 10.1007/s10753-024-02223-y.
KW-2449 is a novel multitargeted kinase inhibitor that has been reported to alleviate chronic inflammation and altered immunity during the treatment of autoimmune diseases. The aim of the study was to investigate the effect of KW-2449 on sepsis-induced cardiomyopathy (SIC). A rat model of moderate SIC was induced using the cecal ligation and puncture (CLP) method. KW-2449 was administered to rats at 10 mg/kg for 3 consecutive days by intraperitoneal injection. At 24 hours after CLP, echocardiography, electrocardiogram, and hemodynamic analyses were performed. Blood and cardiac tissues were collected for further analysis. RNA sequencing (RNA-seq) analyses were used to identify the key genes affected by KW-2449 treatment during SIC. KW-2449 improved the liver dysfunction in septic rats. KW-2449 significantly improved left ventricular (LV) systolic function and hemodynamics compared to the CLP group. KW-2449 suppressed the systemic inflammatory response, decreased myocardial inflammation and cell apoptosis in the CLP rats. RNA-seq analyses indicated that there were a total of 2256 differentially expressed genes in the CLP group compared to the Control group, among which 63 genes were down-regulated and 59 genes were up-regulated by KW-2449. Specifically, Pparα was identified as a key target gene of KW-2449 in the treatment of SIC by RNA-seq analysis.KW-2449 also significantly upregulated the protein expression of Pparα in the LV tissue of septic rats. KW-2449 reduced systemic inflammation, cardiac inflammation, and improved cardiac dysfunction in the CLP-induced SIC rat model. The underlying mechanism of the cardio-protective role of KW-2449 in the CLP-induced SIC might be related to Pparα.
KW-2449是一种新型多靶点激酶抑制剂，据报道在自身免疫性疾病治疗过程中可减轻慢性炎症并改善免疫功能。本研究旨在探讨KW-2449对脓毒症诱导的心肌病（SIC）的影响。采用盲肠结扎穿孔（CLP）法建立中度SIC大鼠模型。通过腹腔注射以10mg/kg的剂量连续3天给大鼠施用KW-2449。在CLP术后24小时，进行超声心动图、心电图和血流动力学分析。采集血液和心脏组织用于进一步分析。RNA测序（RNA-seq）分析用于鉴定在SIC期间受KW-2449治疗影响的关键基因。KW-2449改善了脓毒症大鼠的肝功能障碍。与CLP组相比，KW-2449显著改善了左心室（LV）收缩功能和血流动力学。KW-2449抑制了全身炎症反应，减少了CLP大鼠的心肌炎症和细胞凋亡。RNA-seq分析表明，与对照组相比，CLP组共有2256个差异表达基因，其中63个基因被KW-2449下调，59个基因被上调。具体而言，通过RNA-seq分析确定Pparα是KW-2449治疗SIC的关键靶基因。KW-2449还显著上调了脓毒症大鼠LV组织中Pparα的蛋白表达。KW-2449减轻了CLP诱导的SIC大鼠模型中的全身炎症、心脏炎症，并改善了心脏功能障碍。KW-2449在CLP诱导的SIC中发挥心脏保护作用的潜在机制可能与Pparα有关。
