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Cardiac macrophage CD163 protects pressure overload-induced heart failure via interleukin-10

ABSTRACT: Cardiac macrophages (cMacs) elimination exacerbates pressure overload-induced heart failure. However, the role of functionally distinct subsets of cMacs in heart failure remains largely unknown. CD163, a macrophage-specific scavenger receptor expressed in a subset of cMacs, has been associated with cardiovascular events through its circulating soluble form. This study aimed to elucidate the functional role of the CD163+ cMacs subset in pressure overload-induced heart failure. Transverse aortic constriction (TAC) was used to induce pressure overload. TAC-induced left ventricular systolic dysfunction, characterized by 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 in Cd163−/− mice and improved mitochondrial functions in cardiomyocytes. Furthermore, decreased IL-10 levels and increased soluble CD163 were identified as risk factors for heart failure in hypertensive patients. Thus, CD163 in cMacs attenuates pressure overload-induced left ventricular systolic dysfunction through IL-10.

ORGANISM(S): Mus musculus

PROVIDER: GSE223346 | GEO | 2025/05/08

REPOSITORIES: GEO

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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:Aims: Cardiomyocyte-specific nitric oxide synthase 3 (NOS3) overexpression reduces left ventricular (LV) remodelling after myocardial infarction in mice, but its effect on sustained LV pressure-overload remains incompletely understood. We investigated LV structural and functional adaptation to elevated afterload in mice with cardiomyocyte-restricted NOS3 overexpression (NOS3TG) and wild type littermates (WT). Methods and Results: Hemodynamic indices, cardiac hypertrophy and interstitial fibrosis were measured 10 weeks after transverse aortic constriction (TAC). After 10 weeks TAC, NOS3TG had better preserved systolic function (maximum rates of pressure development normalized to maximal pressure 77Â±6 versus 65Â±2 ms-1, P=0.05), reduced heart weight-body weight ratio (HW/BW, 5.0Â±0.3 versus 5.8Â±0.1, P<0.05), and cardiomyocyte width than WT (14.9Â±0.4 vs 16.7Â±0.2 ?m, P<0.05). After 10 weeks TAC, a 44k cDNA chip-based microarray analysis was validated using real time PCR and revealed significantly altered expression pattern of genes involved in cellular growth, matrix remodelling, and inflammation between genotypes. Conclusions: Cardiomyocyte-restricted NOS3 overexpression attenuates TAC-induced hypertrophy via autocrine inhibition of cardiomyocyte cell growth, but does not mitigate myocardial fibrosis. The subsequent diastolic dysfunction suggests that inhibition of matrix producing cells during hypertrophic stress is necessary to prevent functional and structural deterioration of the pressure-overloaded heart. Left ventricular mRNA expression profiles were compared between alpha-myosin heavy chain driven nitric oxide synthase 3 (alpha-MHC-NOS3) transgenic and wild type (WT) littermate mice at baseline and 10 weeks after transversal aortic constrcition-induced pressure-overload. Biological repeats: n=4, two males and two females, for each group and condition. Transgenic mice were backcrossed for seven generations (F7) to a C57Bl/6 N background and age and weight matched animals were used for microarray experiments.

Project description:Aims: Cardiac hypertrophy is a compensatory response to pressure overload, leading to heart failure. Recent studies have demonstrated that Rho is immediately activated in left ventricles after pressure overload, and that Rho signaling plays crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. However, the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain not fully understood. In this study, we identified the pivotal roles of mammalian homologue of Drosophila diaphanous (mDia) 1, a Rho-effector molecule, in pressure overload-induced ventricular hypertrophy. Methods and Results: Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10–12 weeks old) were subjected to a transverse aortic constriction (TAC) or sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Importantly, we could not observe apparent defects in cardiac hypertrophic responses in mDia3-knockout mice. Microarray analysis revealed that mDia1 was involved in the induction of hypertrophy related genes, including immediate early genes (IEGs), in pressure overloaded hearts. Loss of mDia1 attenuated activation of the mechanotransduction pathway in TAC-operated mice hearts. We also found that mDia1 was involved in stretch-induced activation of the mechanotransduction pathway and gene expression of c-fos in neonatal rat ventricular cardiomyocytes (NRVMs). mDia1 regulated the F/G-actin ratio in response to pressure overload in mice. Additionally, increases in nuclear myocardin-related transcription factors (MRTFs) and serum response factor (SRF) were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs. Conclusions: mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.

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Cardiac macrophage CD163 protects pressure overload-induced heart failure via interleukin-10

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