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.