CD163+ cardiac macrophages attenuate pressure overload-induced left ventricular systolic dysfunction via interleukin-10

Background Chronic sustained pressure overload induces cardiac remodeling, which often leads to heart failure. Cardiac macrophages (cMacs) are heterogeneous cell populations, and their elimination has been shown to exacerbate pressure overload-induced heart failure. CD163, a macrophage-specific scavenger receptor expressed in a subset of cMacs, has been linked to cardiovascular events through its serum soluble form. This study aimed to elucidate the functional role of the CD163+ cMacs subset in pressure overload-induced heart failure. Methods Transverse aortic constriction (TAC) was performed on wild-type and CD163-deficient (Cd163-/-) mice to investigate the role of CD163 in pressure overload-induced cardiac remodeling and heart failure. Echocardiography was used to assess heart structure and function. Transcriptomic analysis and transmission electron microscopy were employed to observe mitochondrial structure in cardiomyocytes. Flow cytometry was used to quantify cMacs and cytokine-expressing cMacs in the heart. Additionally, serum samples from hypertensive patients with and without heart failure were analyzed to explore the relationship between CD163 and heart failure. Results TAC-induced left ventricular systolic dysfunction, including reduced ejection fraction and fractional shortening, was significantly aggravated in Cd163-/- mice post-surgery. Genes differentially expressed due to CD163 deficiency were enriched in pathways related to mitochondrial bioenergetics and homeostasis. Transmission electron microscopy revealed an increase in dysfunctional mitochondria in cardiomyocytes of Cd163-/- mice post-TAC. Additionally, decreased serum interleukin (IL)-10 levels and reduced IL-10 expression in cMacs were observed in Cd163-/- mice post-TAC. IL-10 supplementation significantly reversed TAC-induced reductions in left ventricular systolic function and improved mitochondrial bioenergetics and homeostasis in Cd163-/- mice. Conclusions The protective functions of CD163 in cMacs are associated with IL-10 expression during pressure overload-induced heart failure. TAC was performed as previous report. Briefly, 8-week-old male mice were anesthetized with 2% isoflurane and incubated with 0.5–1 L/min oxygen mixed with 1.5–2% isoflurane during surgery. The transverse aorta was exposed and tied with a 27-gauge blunt needle by 6-0 silk string. The needle was removed later. The chest and skin were closed, and mice were allowed to recover from anesthesia. Sham surgery was carried out as above without aortic ligation. Cd163-/- mice received subcutaneous injections of mouse recombinant IL-10 (50 μg/kg/day) on days 0, 1, 3, 5, 7, 10, 13, 16, 19, 22, 25, and 27 following TAC surgery. Peritoneal macrophages were harvested from the peritoneal cavity three days after stimulation with thioglycolate-containing medium (16). Following centrifugation, the macrophages were cultured in Dulbecco's modified Eagle medium (DMEM) supplemented with 5% fetal bovine serum (FBS) and 1% penicillin-streptomycin (P/S) at 37 °C in a 5% CO₂ environment. The cells were allowed to adhere for 2–3 hours, and non-adherent cells were removed. After overnight culture, the adherent cells were treated with 100 nM dexamethasone for 48 hours.