CD163 macrophages attenuate pressure overload-induced left ventricular systolic dysfunction and cardiac mitochondrial dysfunction via interleukin-10.

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.