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Macrophage Cluster of Differentiation 163 promotes post-infarction cardiac repair and preserves left ventricular function via osteopontin

ABSTRACT: Background: Cardiac macrophages have been implicated in myocardial repair following myocardial infarction (MI), yet their therapeutic potential in ischemic cardiomyopathy (ICM) remains limited by an incomplete understanding of their molecular regulation. CD163 is highly expressed in these macrophages, yet its functional role in regulating post-MI cardiac repair remains unknown. Methods: A cross-sectional clinical study was conducted to assess the association between circulating soluble CD163 concentration and heart failure due to ICM. To investigate the functional contribution of CD163 in ICM, Wild-type (WT) and Cd163/ mice were subjected to permanent ligation of the left anterior descending coronary artery. Single-cell RNA sequencing was employed to analyze transcriptional changes in cardiac immune cells. Recombinant osteopontin (OPN) and CD163 were administered to assess their therapeutic effect in Cd163/ mice. Results: Circulating soluble CD163 levels were markedly elevated in patients with ICM-induced heart failure compared with individuals without heart failure (median difference 34.5 ng/mL, IQR 13.6–54.6 ng/mL, P = 0.002) and showed a positive correlation with the extent of systolic dysfunction and left ventricular dilation. Cd163/ mice displayed aggravated left ventricular systolic dysfunction, reduced ejection fraction and fractional shortening, impaired myocardial strain, and reduced relative wall thickness post-MI. Recombinant CD163 protein could reverse systolic dysfunction and left ventricular dilation in Cd163/ mice after MI. CD163 was predominantly expressed in CCR2⁻ resident cardiac macrophages, and CD163 deficiency altered transcriptional programs of macrophages without affecting their polarization status, with enrichment in cytokine signaling and extracellular matrix-related pathways. Spp1 (OPN) expression was significantly downregulated in Cd163/ hearts under both sham and MI conditions. Administration of recombinant OPN improved systolic function, reduced ventricular dilation, decreased fibrotic scar size, and restored the elastin-to-collagen ratio in Cd163/ mice. Conclusions: In cardiac macrophages, CD163 contributes to post-myocardial infarction repair by upregulating OPN expression, which in turn helps maintain systolic function.

ORGANISM(S): Mus musculus

PROVIDER: GSE306718 | GEO | 2026/04/18

REPOSITORIES: GEO

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Project description:Background: Myocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an ECM protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown. Methods: Three microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast–macrophage co-culture model in vitro. Results: ITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast–macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages. Conclusions: ITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.

Project description: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.

Project description:BACKGROUND: Despite significant advances in acute care medicine, myocardial infarction (MI) remains a predominant cause of premature death and heart failure. In the infarct border zone, cardiomyocytes are exposed to high biomechanical stress that impairs the integrity of the sarcolemmal membrane. Here, we hypothesized that the Ca2+-sensitive membrane repair protein dysferlin is key to preserving sarcolemmal nanodomains like the transverse-axial tubule (TAT) endomembrane network and the intercalated disc (ICD) membrane folds in the infarct border zone. METHODS: We employed permanent left anterior descending artery ligation to induce MI in mice, and used data-independent acquisition mass spectrometry (DIA-MS) to analyze the spatial proteomic profile in wild-type versus dysferlin-knockout hearts post-MI. Stimulated emission depletion (STED) nanoscopy and electron tomography were applied to study membrane nanodomain remodeling and dissect the role of dysferlin in local membrane protection and repair in cardiomyocytes of the infarct border zone. Co-immunoprecipitation-based DIA-MS and complexome profiling were used to further decode the cardiac interactome of dysferlin. RESULTS: DIA-MS quantitatively analyzed 5,700 proteins, segregating the proteomic profiles of the left-ventricular infarct zone, border zone and remote zone in wild-type versus dysferlin-knockout mice one week post-MI. While dysferlin protein expression was significantly upregulated in the MI border and remote zone, dysferlin-knockout mice presented larger infarct sizes and reduced left-ventricular systolic function post-MI. In cardiomyocytes of the WT infarct border zone, STED nanoscopy visualized severely disrupted TAT membranes and enlarged ICD membrane folds. Importantly, extensive dysferlin signals clustered in nanometric proximity to residual TAT structures and connexin-43 plaques at the ICD, stabilizing functional nanodomain organization for preserved excitation-contraction coupling and intercellular communication. Interactomic analyses revealed connexin-43 as a novel dysferlin interaction partner.

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Macrophage Cluster of Differentiation 163 promotes post-infarction cardiac repair and preserves left ventricular function via osteopontin

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