Exercise Training Protects Against Heart Failure Via Expansion of Myeloid-Derived Suppressor Cells Through Regulating IL-10/STAT3/S100A9 Pathway

2021 ◽  
Author(s):  
Lifeng Feng ◽  
Guangru Li ◽  
Jiale An ◽  
Chang Liu ◽  
Xiaolong Zhu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Western Blot ◽  
Protective Effect ◽  
Calcium Binding ◽  
Cardiac Fibrosis ◽  
Heart Function ◽  
Suppressor Cells ◽  
Inflammatory Factors ◽  
Myeloid Derived Suppressor Cells

Background: Exercise training (ET) has a protective effect on the progression of heart failure, however, the specific mechanism has not been fully explored. Myeloid-derived suppressor cells (MDSCs) are a group of myeloid-derived immunosuppressive cells, which showed a protective effect in the progression of heart failure. Thus, we hypothesized that the protective effect of ET on heart failure may be related to the infiltration of MDSCs. Methods: C57BL/6 mice were made to run on a treadmill 6× a week for 4 weeks followed by isoproterenol injection from third week. Heart function was evaluated by echocardiography and the proportion of MDSCs was detected by flow cytometry. Hypertrophic markers, cardiac fibrosis, and inflammatory factors were detected by real-time PCR, ELISA, histological staining, and Western blot. Results: ET treatment in isoproterenol-induced heart failure mice (n=7) enhanced cardiac function (57% increase in FS%, P =0.002) and improved morphological changes compared with isoproterenol mice (n=17). ET further caused 79% increasing in cardiac MDSCs in isoproterenol mice ( P <0.001). In addition, depletion of MDSCs by 5-Fluorouracil blunted the cardio-protective effect of ET. T-cell proliferation assay showed that ET did not affect the suppressive activity of MDSCs. Furthermore, we found that ET activated the secretion of IL (interleukin)-10 by macrophages in isoproterenol mice. MDSCs expansion and cardio protection was not present in tamoxifen-inducible macrophage-specific IL-10 knockout mice. Western blot results confirmed that IL-10 regulated the differentiation of MDSCs through the translocation of p-STAT3 (signal transducer and activator of transcription 3)/S100A9 (S100 calcium-binding protein A9) to the nucleus. Conclusions: ET could increase MDSCs by stimulating the secretion of IL-10 from macrophage, which was through IL-10/STAT3/S100A9 signaling pathway, thereby achieving the role of heart protection.

Abstract 10: Antifibrotic Effect of CCN5 in a Murine Model of Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Dongtak Jeong ◽  
Changwon Kho ◽  
Ahyoung Lee ◽  
Woo Jin Park ◽  
Roger Hajjar
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Western Blot ◽  
Cardiac Fibrosis ◽  
Cell Function ◽  
Heart Function ◽  
Pcr Analysis ◽  
Tgf Beta ◽  
Human Heart Failure ◽  
Ccn Family

CCN family members are matricellular proteins with diverse roles in cell function. Recently, we showed that the differential expression of CCN2 and CCN5 during cardiac remodeling suggests that these two members of the CCN family play opposing roles during the development of cardiac hypertrophy and fibrosis. Since it is reported that an underlying morphological correlate of diastolic dysfunction is cardiac fibrosis, which leads to increased stiffness of the heart, we aimed to evaluate the role of CCN5 on cardiac fibrosis and function by the gene delivery using the cardiotropic AAV9 vector. We generated pressure-overload heart failure models in mouse by TAC operation. After 8-10 weeks of TAC on mice, HF was confirmed by Echocardiography. In those HF mice, AAV9-GFP (control) and AAV9-CCN5 were addressed by IV. Two more months later, cardiac function was evaluated by echocardiography and invasive hemodynamics. Protein and RNA expression levels of CCN5, several types of collagen and conventional TGF-beta signaling related genes were evaluated by western blot and quantitative real time PCR analysis. First, we were able to achieve about 4-5 fold increase of CCN5 expression by AAV9-CCN5 injection without any change in heart function. Second, CCN5 expression level in blood was not significantly altered after AAV9-CCN5 gene transfer because it may be the result of the cardiac tropism of the vector used. The HF model by TAC surgery was confirmed with echocardiography (FS (%)). Overall average FS (%) in HF was 41.87+/− 5.27 (n=16) and in non-surgery control mice was 58.39 +/− 2.06(n=4). After AAV9 injection, cardiac function of CCN5 injected mice was sustained but AAV9-GFP injected mice showed severe cardiac dysfunction and dilation (AAV-GFP (24.29+/− 9.11) vs AAV-CCN5 (42.66 +/− 4.73)). Third, western blot analysis showed that the downstream effectors, namely TGF-beta signaling pathways were significantly down-regulated in CCN5 injected mice. In addition, fibrotic area of the heart was tremendously reduced. Finally, CCN5 expression is significantly decreased in human heart failure patients compared to those in nonfailing donors. Taken together our data would indicate that CCN5 may be a promising therapeutic target to reduce cardiac fibrosis.

Metabolic changes and interaction of tumor cell, myeloid-derived suppressor cell and T cell in hypoxic microenvironment

2020 ◽  
Author(s):  
Xiantu Ou ◽  
Weibiao Lv
Keyword(s):  
Tumor Microenvironment ◽  
Regulatory Protein ◽  
Tumor Hypoxia ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Inflammatory Factors ◽  
Tumor Escape ◽  
Myeloid Derived Suppressor Cells ◽  
Myeloid Derived Suppressor Cell ◽  
Transcriptional Regulatory

It is universally acknowledged that a large number of immune cells, as well as inflammatory factors, regulatory factors and metabolites, accumulate in the tumor microenvironment to jointly promote tumor escape, development and metastasis. Hypoxia is one of the characteristics in tumor microenvironment and is a common phenomenon in all solid tumors. In tumor hypoxia response, there is a key regulator called HIF-1a, which is a key transcriptional regulatory protein that regulates many critical genes. In this paper, the effects of hypoxia on glucose metabolism of tumor cells, myeloid-derived suppressor cells and T cells in tumor microenvironment were reviewed, and the interaction among the three was also described.

scholarly journals Letter by Moris et al Regarding Article, “Cardioprotective Role of Myeloid-Derived Suppressor Cells in Heart Failure”

Circulation ◽  
2019 ◽  
Vol 139 (2) ◽  
pp. 299-300
Author(s):  
Dimitrios Moris ◽  
Georgia-Sofia Karachaliou ◽  
Georgios Karaolanis
Keyword(s):  
Heart Failure ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells

scholarly journals Effects of enteral nutrition on heart function, inflammatory markers and immune function in elderly patients with chronic heart failure

2021 ◽  
Vol 38 (1) ◽  
Author(s):  
Dan Zhang ◽  
Hongli Li ◽  
Xiang Tian ◽  
Sujuan Zhang
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Enteral Nutrition ◽  
Elderly Patients ◽  
Immune Function ◽  
Inflammatory Markers ◽  
Heart Function ◽  
Inflammatory Factors ◽  
Control Group ◽  
Experimental Group

Objectives: To evaluate the effect of enteral nutrition on heart function, inflammatory markers and immune function in elderly patients with chronic heart failure and its clinical significance. Methods: Eighty patients with moderate and severe heart failure admitted to the Cardiology Intensive Care Unit (CCU) of Baoding First Central Hospital from May 2019 to May 2020 were included in this study and randomly divided into two groups: the experimental group and the control group, with 40 patients in each group. The experimental group was given enteral nutrition support therapy on the basis of conventional therapy for one month, while the control group was given restricted salt and water intake on the basis of conventional therapy, and patients were given free diet according to their wishes. The changes in heart function before and after treatment, changes in inflammatory factors such as TNF-a, CRP, IL-6, changes in levels of immunoglobulins such as IgA, IgM, and IgG, and the improvement of the performance status of the two groups were compared and analyzed. Results: After treatment, indicators such as BNP, LVEDD, LVEF and 6min walking distance in the experimental group were significantly improved compared with the control group, with statistically significant differences (p<0.05), and the levels of inflammatory factors such as TNF-a, CRP and IL-6 in the experimental group were significantly reduced compared with those in the control group (p=0.00). The levels of IgG, IgA, IgM and other immunoglobulins in the experimental group improved more significantly after treatment than those in the control group, with statistically significant differences (IgG, IgA, p=0.00; IgM, p=0.01). Moreover, the experimental group was significantly superior to the control group in the improvement rate of performance status score (ECOG) after treatment (p=0.04); The incidence of gastrointestinal adverse reactions in the experimental group was 20%, and that in the control group was 15%. No statistically significant difference can be observed in the gastrointestinal tolerance of both groups (p=0.56). Conclusions: Reasonable enteral nutrition boasts a variety of benefits for the recovery of elderly patients with chronic heart failure. With reasonable enteral nutrition, the heart function of elderly patients with chronic heart failure can be significantly improved, inflammatory factors can be reduced, immunity and performance status can be enhanced, and gastrointestinal tolerance can be ameliorated without obvious gastrointestinal reactions. doi: https://doi.org/10.12669/pjms.38.1.4451 How to cite this:Zhang D, Li H, Tian X, Zhang S. Effects of enteral nutrition on heart function, inflammatory markers and immune function in elderly patients with chronic heart failure. Pak J Med Sci. 2022;38(1):---------.  doi: https://doi.org/10.12669/pjms.38.1.4451 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Impact of exercise training on ventricular properties in a canine model of congestive heart failure

1997 ◽  
Vol 272 (3) ◽  
pp. H1382-H1390 ◽  
Author(s):  
K. Todaka ◽  
J. Wang ◽  
G. H. Yi ◽  
M. Knecht ◽  
R. Stennett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Heart Function ◽  
Systolic Pressure ◽  
Cardiac Pacing ◽  
Left Ventricular ◽  
Lv Function ◽  
Myocardial Stiffness

Exercise training improves functional class in patients with chronic heart failure (CHF) via effects on the periphery with no previously documented effect on intrinsic left ventricular (LV) properties. However, because methods used to evaluate in vivo LV function are limited, it is possible that some effects of exercise training on the failing heart have thus far eluded detection. Twelve dogs were instrumented for cardiac pacing and hemodynamic recordings. Hearts were paced rapidly for 4 wk. Six of the dogs received daily treadmill exercise (CHF(EX), 4.4 km/h, 2 h/day) concurrent with rapid pacing, while the other dogs remained sedentary (CHFs). Hemodynamic measurements taken in vivo at the end of 4 wk revealed relative preservation of maximum rate of pressure rise (2,540 +/- 440 vs. 1,720 +/- 300 mmHg/s, P < 0.05) and LV end-diastolic pressure (9 +/- 5 vs. 19 +/- 4 mmHg, P < 0.05) in CHF(EX) compared with CHFs. The hearts were then isolated and cross perfused for in vitro measurement of isovolumic pressure-volume relations; these results were compared with those of six normal dogs (N). Systolic function was similarly depressed in both groups of pacing animals [end-systolic elastance (Ees) values of 1.66 +/- 0.47 in CHFs, 1.77 +/- 0.38 in CHF(EX), and 3.05 +/- 0.81 mmHg/ml in N, with no changes in volume axis interceptors of the end-systolic pressure-volume relationship]. The diastolic myocardial stiffness constant, k, was elevated in CHFs and was normalized by exercise training (32 +/- 3 in CHFs, 21 +/- 3 in CHF(EX), 20 +/- 4 in N). Thus daily exercise training preserved in vivo hemodynamics during 4 wk of rapid cardiac pacing and was accompanied by a significant change in diastolic myocardial stiffness in vitro. These findings suggest that changes in heart function may contribute to the overall beneficial hemodynamic effects of exercise training in CHF by a significant effect on diastolic properties.

Myeloid Derived Suppressor Cells (MDSCs) Are Increased and Exert Immunosuppressive Activity In CML Patients At Diagnosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2711-2711
Author(s):  
Cesarina Giallongo ◽  
Nunziatina Parrinello ◽  
Daniele Tibullo ◽  
Piera La Cava ◽  
Alessandra Romano ◽  
...  
Keyword(s):  
T Cell ◽  
Western Blot ◽  
Cell Function ◽  
Conflicts Of Interest ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Immunosuppressive Activity ◽  
Arginase 1

Abstract Introduction In some solid tumors it has been demonstrated that a subpopulation of myeloid cells, defined as “myeloid-derived suppressor cells” (MDSCs), plays an important role in inducing T cell tolerance by production of arginase 1 (arg1) that depletes microenvironment of arginine, an essential aminoacid for T cell function. Since chronic myeloid leukemia (CML) patients have high levels of immature myeloid cells it is of interest to investigate if these cells have MDSCs phenotype and activity. The aim of this study was to analyze MDSCs and investigate their activity in CML patients. Methods MDSCs were analyzed in peripheral blood (PB) of 20 healthy donors (HD) and 30 CML patients at diagnosis. In 21 patients MDSCs were also measured during TKI treatment. Granulocytic MDSCs (G-MDSCs) were identified as CD11b+CD33+CD14-HLADR- cells, while the monocytic MDSCs (Mo-MDSCs) as CD14+HLADR by cytofluorimetric analysis. Arg1 expression was assessed using real time PCR and Western Blot. Arg activity was measured in granulocyte lysates using a colorimetric test after enzymatic activation and arginine hydrolysis. Microvesicles (MV) were isolated from CML serum at diagnosis (n=5) by sequential ultracentrifugation. Results CML patients showed high levels of Mo- and G-MDSCs at diagnosis in comparison to HD (41±8 and 82,5±12,2% respectively for CML vs 9±2,1 and 55±5,3% for HD; p<0.001), while after TKIs therapy both subpopulations decreased, returning to normal values. T-reg (CD4+ CD25high Foxp3+ cells) were also significantly increased in CML patients at diagnosis in respect to HD (9±2% vs 6,1±0,8%, p<0.001) with a significant correlation with the percentage of Gr-MDSCs (r=0,6254; p<0.001). Both in PB and purified granulocytic cells, Arg1 expression showed a 30 fold increase in CML at diagnosis compared to HD (p<0.001) and decreased after therapy. The same data were confirmed by Western Blot analysis. Arg enzymatic activity in granulocytes resulted also increased in CML (n=10) compared to HD (n=10) (p<0.001). The suppressive function of CML G-MDSCs was demonstrated by their ability to inhibit the proliferation of CFSE+ HD T cells (p<0.001). In addition, an increase of Mo-MDSCs in vitro was observed after incubation of HD monocytes with CML sera (29±13%; p<0.0001) or MV (8±2,8%; p<0.05). Conclusions MDSCs are increased in CML patients at diagnosis and decrease during TKIs treatment. CML granulocytes have high arg1 activity and immunosuppressive activity. Moreover, CML serum as well as CML microvesicles increase the percentage of HD Mo-MDSCs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Klotho Deficiency Causes Heart Aging via Impairing the Nrf2-GR Pathway

2020 ◽  
Author(s):  
Kai Chen ◽  
Shirley Wang ◽  
Qiwei Wilton Sun ◽  
Bo Zhang ◽  
Mujib Fnu Ullah ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Therapeutic Strategy ◽  
Cardiac Fibrosis ◽  
Heart Function ◽  
Large Population ◽  
Cardiac Aging ◽  
Heart Size ◽  
Old Mice ◽  
Fractional Shortening

Rationale: Cardiac aging is an important contributing factor for heart failure which affects a large population but remains poorly understood. Objective: The purpose of this study is to investigate whether Klotho plays a role in cardiac aging. Methods and Results: Heart function declined in old mice (24 months), as evidenced by decreases in fractional shortening, ejection fraction, and cardiac output. Heart size and weight, cardiomyocyte size and cardiac fibrosis were increased in old mice, indicating that aging causes cardiac hypertrophy and remodeling. Circulating Klotho levels were dramatically decreased in old mice, which prompted us to investigate whether the Klotho decline may cause heart aging. We found that Klotho gene mutation (KL-/-) largely decreased serum klotho levels and impaired heart function. Interestingly, supplement of exogenous secreted Klotho prevented heart failure, hypertrophy, and remodeling in both old mice and KL (-/-) mice. Secreted Klotho treatment inhibited excessive cardiac oxidative stress, senescence and apoptosis in old mice and KL (-/-) mice. Serum phosphate levels in KL (-/-) mice were kept in the normal range, suggesting that Klotho deficiency-induced heart aging is independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed glutathione reductase (GR) expression and activity in the heart via inhibition of transcription factor Nrf2. Furthermore, cardiac-specific overexpression of GR prevented excessive oxidative stress, apoptosis, and heart failure in both old and KL (-/-) mice. Conclusions: Klotho deficiency causes cardiac aging via impairing the Nrf2-GR pathway. Supplement of exogenous secreted Klotho represents a promising therapeutic strategy for aging-associated cardiomyopathy and heart failure.

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