Ni Wei, Ge Xiaofeng, Liu Yang, Chen Jingyu, Wang Lin, Chen Linjian, Li Zhaokai, Zhang Peng, Huang Shufen, Xu Junhui, Zhang Le, Fan Xiabin, Wang Gang, Huang Wei, Ye Yuanchao, Zhou Jiancang, Dai Cuilian, Liu Binbin
School of Medicine, Xiamen Cardiovascular Hospital, Xiamen University, Jinshan Road 2999, Xiamen, 361015, China.
Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Qingchun East Road 3, Hangzhou, 310016, China.
Basic Res Cardiol. 2025 May 9. doi: 10.1007/s00395-025-01114-z.
Macrophage depletion exacerbates pressure overload-induced heart failure, but therapeutic translation is hindered by macrophage subset heterogeneity. The functional role of CD163 macrophages in heart failure remains unclear. Transverse aortic constriction (TAC) was employed to induce pressure overload. Cd163 mice exhibited significantly aggravated TAC-induced left ventricular systolic dysfunction, as demonstrated by reduced ejection fraction, fractional shortening, and global longitudinal strain, compared to wild-type (WT) controls. RNA sequencing of cardiac tissues revealed significant differential gene expression between TAC-treated WT and Cd163 mice, especially in pathways governing mitochondrial bioenergetics and homeostasis. Transmission electron microscopy confirmed greater accumulation of dysfunctional mitochondria in cardiomyocytes of Cd163 mice relative to WT following TAC. Additionally, the proportion of CD163 macrophages among cardiac macrophages increased post-TAC. Serum IL-10 levels and cardiac macrophage IL-10 expression were significantly diminished in Cd163 mice compared to WT after TAC. IL-10 supplementation effectively reversed the TAC-induced impairment in left ventricular systolic function in both WT and Cd163 mice, and reduced NADH/NAD ratios, reduced mitochondrial dysfunction, and improved mitochondrial membrane potential in Cd163 mice. Cross-sectional clinical data supported these findings, showing decreased IL-10 levels as a significant risk factor for heart failure in hypertensive patients (odds ratio: 0.397; 95% CI 0.203-0.775; p = 0.007). Collectively, these results highlight the protective role of CD163 macrophages against pressure overload-induced left ventricular dysfunction and mitochondrial dysfunction through IL-10-dependent pathways.
巨噬细胞耗竭会加剧压力超负荷诱导的心力衰竭，但巨噬细胞亚群的异质性阻碍了其治疗转化。CD163巨噬细胞在心力衰竭中的功能作用仍不清楚。采用横向主动脉缩窄（TAC）诱导压力超负荷。与野生型（WT）对照相比，Cd163小鼠表现出TAC诱导的左心室收缩功能障碍显著加重，表现为射血分数、缩短分数和整体纵向应变降低。心脏组织的RNA测序显示，TAC处理的WT小鼠和Cd163小鼠之间存在显著的差异基因表达，尤其是在控制线粒体生物能量学和内环境稳定的途径中。透射电子显微镜证实，TAC后，Cd163小鼠心肌细胞中功能失调的线粒体相对于WT小鼠有更多积累。此外，TAC后心脏巨噬细胞中CD163巨噬细胞的比例增加。与WT小鼠相比，TAC后Cd163小鼠的血清IL-10水平和心脏巨噬细胞IL-10表达显著降低。补充IL-10有效逆转了WT小鼠和Cd163小鼠TAC诱导的左心室收缩功能损害，并降低了Cd163小鼠的NADH/NAD比率，减少了线粒体功能障碍，改善了线粒体膜电位。横断面临床数据支持了这些发现，显示IL-10水平降低是高血压患者心力衰竭的一个重要危险因素（比值比：0.397；95%可信区间0.203-0.775；p=0.007）。总体而言，这些结果突出了CD163巨噬细胞通过IL-10依赖途径对压力超负荷诱导的左心室功能障碍和线粒体功能障碍的保护作用。
