scholarly journals Blockade of the Notch Signaling Pathway Promotes M2 Macrophage Polarization to Suppress Cardiac Fibrosis Remodeling in Mice With Myocardial Infarction

2022 ◽  
Vol 8 ◽  
Author(s):  
Zhi Li ◽  
Miao Nie ◽  
Liming Yu ◽  
Dengshun Tao ◽  
Qiang Wang ◽  
...  

Myocardial infarction (MI) is regarded as a serious ischemic heart disease on a global level. The current study set out to explore the mechanism of the Notch signaling pathway in the regulation of fibrosis remodeling after the occurrence of MI. First, experimental mice were infected with recombination signal binding protein J (RBP-J) shRNA and empty adenovirus vector, followed by the establishment of MI mouse models and detection of cardiac function. After 4 weeks of MI, mice in the sh-RBP-J group were found to exhibit significantly improved cardiac function relative to the sh-NC group. Moreover, knockdown of RBP-J brought about decreased infarct area, promoted cardiac macrophages M2 polarization, reduced cardiac fibrosis, and further decreased transcription and protein expressions of inflammatory factors and fibrosis-related factors. Furthermore, downregulation of cylindromatosis (CYLD) using si-CYLD reversed the results that knockdown of RBP-J inhibited fibrogenesis and the release of inflammatory factors. Altogether, our findings indicated that the blockade of Notch signaling promotes M2 polarization of cardiac macrophages and improves cardiac function by inhibiting the imbalance of fibrotic remodeling after MI.

Author(s):  
Sifeng Tao ◽  
Qiang Chen ◽  
Chen Lin ◽  
Haiying Dong

Abstract Background Tumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment. M2 polarization of TAMs, which is a major actor in breast cancer malignancy and metastasis, can be induced by breast cancer cells. However, the potential mechanisms of the interaction between breast cancer cells and TAMs remain unclear. Methods The candidate breast cancer-associated long non-coding RNAs (lncRNAs) were analyzed using the GEO database. Functional assays, including MTT assay, Transwell assay, and EdU labeling detection, were performed to investigate the oncogenic role of linc00514 in breast cancer progression. The co-culture and ELISA assays were used to assess the role of linc00514 in macrophage recruitment and M2 polarization. RNA immunoprecipitation, RNA pull-down, and luciferase reporter assays were applied to determine the mechanism of linc00514 in breast cancer metastasis. Mouse xenograft models, mouse pulmonary metastatic models, and mouse primary tumor models were used to assess the role of linc00514 in M2 macrophage polarization and breast cancer tumorigenicity. Results Linc00514 was highly expressed in clinical breast cancer tissues and breast cancer cell lines. Overexpression of linc00514 promoted the proliferation and invasion of breast cancer cells and increased xenograft tumor volumes and pulmonary metastatic nodules. Overexpression of linc00514 also increased the percentage of macrophages expressing M2 markers CD206 and CD163. Mechanistically, linc00514 promoted Jagged1 expression in a transcriptional manner by increasing the phosphorylation of a transcription factor STAT3. Subsequently, Jagged1-mediated Notch signaling pathway promoted IL-4 and IL-6 secretions in breast cancer cells and ultimately inducing M2 polarization of macrophages. Conclusion Linc00514 plays an important role in regulating breast cancer tumorigenicity and M2 macrophage polarization via Jagged1-mediated Notch signaling pathway.


2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jialiang Zhang ◽  
Fangyang Huang ◽  
Li Chen ◽  
Guoyong Li ◽  
Wenhua Lei ◽  
...  

Background. After myocardial infarction, anti-inflammatory macrophages perform key homeostatic functions that facilitate cardiac recovery and remodeling. Several studies have shown that lactate may serve as a modifier that influences phenotype of macrophage. However, the therapeutic role of sodium lactate in myocardial infarction (MI) is unclear. Methods. MI was established by permanent ligation of the left anterior descending coronary artery followed by injection of saline or sodium lactate. Cardiac function was assessed by echocardiography. The cardiac fibrosis area was assessed by Masson trichrome staining. Macrophage phenotype was detected via qPCR, flow cytometry, and immunofluorescence. Signaling proteins were measured by Western blotting. Results. Sodium lactate treatment following MI improved cardiac performance, enhanced anti-inflammatory macrophage proportion, reduced cardiac myocytes apoptosis, and increased neovascularization. Flow-cytometric analysis results reported that sodium lactate repressed the number of the IL-6+, IL-12+, and TNF-α+ macrophages among LPS-stimulated bone marrow-derived macrophages (BMDMs) and increased the mRNA levels of Arg-1, YM1, TGF-β, and IL-10. Mechanistic studies revealed that sodium lactate enhanced the expression of P-STAT3. Furthermore, a STAT3 inhibitor eliminated sodium lactate-mediated promotion macrophage polarization. Conclusion. Sodium lactate facilitates anti-inflammatory M2 macrophage polarization and protects against MI by regulating P-STAT3.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3410
Author(s):  
Seung-Cheol Lee ◽  
Yoo-Jung Lee ◽  
Inho Choi ◽  
Min Kim ◽  
Jung-Suk Sung

Adipocytes interact with adipose tissue macrophages (ATMs) that exist as a form of M2 macrophage in healthy adipose tissue and are polarized into M1 macrophages upon cellular stress. ATMs regulate adipose tissue inflammation by secreting cytokines, adipokines, and chemokines. CXC-motif receptor 6 (CXCR6) is the chemokine receptor and interactions with its specific ligand CXC-motif chemokine ligand 16 (CXCL16) modulate the migratory capacities of human adipose-derived mesenchymal stem cells (hADMSCs). CXCR6 is highly expressed on differentiated adipocytes that are non-migratory cells. To evaluate the underlying mechanisms of CXCR6 in adipocytes, THP-1 human monocytes that can be polarized into M1 or M2 macrophages were co-cultured with adipocytes. As results, expression levels of the M1 polarization-inducing factor were decreased, while those of the M2 polarization-inducing factor were significantly increased in differentiated adipocytes in a co-cultured environment with additional CXCL16 treatment. After CXCL16 treatment, the anti-inflammatory factors, including p38 MAPK ad ERK1/2, were upregulated, while the pro-inflammatory pathway mediated by Akt and NF-κB was downregulated in adipocytes in a co-cultured environment. These results revealed that the CXCL16/CXCR6 axis in adipocytes regulates M1 or M2 polarization and displays an immunosuppressive effect by modulating pro-inflammatory or anti-inflammatory pathways. Our results may provide an insight into a potential target as a regulator of the immune response via the CXCL16/CXCR6 axis in adipocytes.


2021 ◽  
Author(s):  
Hogjuan Ning ◽  
Haixu Chen ◽  
Jingyu Deng ◽  
Chun Xiao ◽  
Lina Shan ◽  
...  

Abstract Background Exosomes are considered a substitute for stem cell-based therapy for myocardial infarction (MI). FNDC5, a transmembrane protein located in the cytoplasm, plays a crucial role in inflammation diseases and MI repair. Furthermore, our previous study found that FNDC5 pre-conditioning bone marrow-derived mesenchymal stem cells (BMMSCs) could secreted more exosomes, but little was known on MI repair. Methods Exosomes isolated from BMMSCs with or without FNDC5-OV were injected into infarcted hearts. Then, cardiomyocytes apoptosis, and inflammation responses were detected. Furthermore, exosomes were administrated to RAW264.7 macrophage with LPS treatment to investigate its effect on inflammation and macrophage polarization. Results Compared with MSCs-Exo, FNDC5-MSCs-Exo had superior therapeutic effects on anti-inflammation and anti-apoptosis, as well as polarizing M2 macrophage in vivo. Meanwhile, the in vitro results also showed that FNDC5-MSCs–Exo decreased pro-inflammatory secretion and increased anti-inflammatory secretion under LPS stimulation, which partly depressed NF-κB signaling pathway and upregulated Nrf2/HO-1 Axis. Conclusions FNDC5-BMMSCs-derived exosomes play anti-inflammation effects and promote M2 macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis, which may develop a promising cell-free therapy for MI.


Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 2016 ◽  
Author(s):  
Wei Wei ◽  
Zhi-Peng Li ◽  
Zhao-Xiang Bian ◽  
Quan-Bin Han

Macrophages occur in polarized phenotypes, whose characteristics determine the role they play in tumor growth. The M1 phenotype macrophages promote tumoricidal responses and suppress tumor growth. Our previous study showed that a polysaccharide isolated from Radix Astragali, named RAP, was itself non-cytotoxic but induced RAW264.7 cells’ cytotoxicity against cancer cells. The current study was undertaken to determine its mechanism. Series studies was conducted to show that RAP is able to induce much higher gene expression of M1 markers, including iNOS, IL-6, TNF-a, and CXCL10, compared with the control group. When RAP-induced BMDMs were transplanted together with 4T1 tumor cells in BALB/c mice, both tumor volume and tumor weight decreased. Further studies indicated that RAP induces the Notch signaling pathway in RAW264.7 cells. The function of Notch signaling in macrophage polarization was confirmed by using γ-secretase inhibitor. These results suggested that Astragalus polysaccharide RAP induces macrophage’s polarization to M1 phenotype via the Notch signaling pathway.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Liu ◽  
Xuehui Zheng ◽  
Chen Zhang ◽  
Chunmei Zhang ◽  
Peili Bu

Background: Lcz696 (ARNI, angiotensin receptor–neprilysin inhibitor; sacubitril/valsartan) shows an inhibitory effect on fibrosis after myocardial infarction (MI). However, the underlying signaling mechanisms are poorly understood. The Wnt/β-catenin signaling pathway is activated after MI and participates in the process of myocardial fibrosis. Here, we aimed to assess the efficacy of ARNI for alleviating myocardial fibrosis after MI and hypothesized that ARNI alleviates myocardial fibrosis by inhibiting the Wnt/β-catenin signaling pathway and overexpressing sFRP-1, an inhibitor of the Wnt/β-catenin signaling pathway.Methods: Mice randomized at 1 week post-MI were administered lcz696 (60 mg/kg, n = 21), valsartan (30 mg/kg, n = 19), or corn oil (n = 13) orally for 4 weeks, while the sham-operated group received vehicle (corn oil, n = 19). Cardiac function and extent of myocardial fibrosis were measured. Western blotting and quantitative real-time polymerase chain reaction were used to detect the expression of Wnt/β-catenin pathway-related proteins. Furthermore, primary myocardial fibroblasts were stimulated with angiotensin II (Ang II) and cultured with lcz696 and the sFRP-1 inhibitor way316606 to detect the expression of Wnt/β-catenin pathway proteins.Results: Both lcz696 and valsartan alleviated myocardial fibrosis and improved cardiac function, but lcz696 had superior efficiency compared to valsartan. Furthermore, β-catenin expression was inhibited and sFRP-1 was overexpressed after drug treatment, which could be significantly improved by lcz696 in mice. In addition, lcz696 inhibited β-catenin expression in AngII-stimulated myocardial fibroblasts, and β-catenin expression increased after the inhibition of sFRP-1.Conclusion: ARNI alleviated cardiac fibrosis and cardiac remodeling by inhibiting the Wnt/β-catenin signaling pathway. In addition, ARNI can lead to overexpression of sFRP-1, which is an inhibitor of the Wnt/β-catenin signaling pathway. These results indicate a new therapeutic target of ARNI to improve myocardial fibrosis and prevent myocardial remodeling.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hongjuan Ning ◽  
Haixu Chen ◽  
Jingyu Deng ◽  
Chun Xiao ◽  
Moyan Xu ◽  
...  

Abstract Background Exosomes are considered a substitute for stem cell-based therapy for myocardial infarction (MI). FNDC5, a transmembrane protein located in the cytoplasm, plays a crucial role in inflammation diseases and MI repair. Furthermore, our previous study found that FNDC5 pre-conditioning bone marrow-derived mesenchymal stem cells (BMMSCs) could secrete more exosomes, but little was known on MI repair. Methods Exosomes isolated from BMMSCs with or without FNDC5-OV were injected into infarcted hearts. Then, cardiomyocytes apoptosis and inflammation responses were detected. Furthermore, exosomes were administrated to RAW264.7 macrophage with LPS treatment to investigate its effect on inflammation and macrophage polarization. Results Compared with MSCs-Exo, FNDC5-MSCs-Exo had superior therapeutic effects on anti-inflammation and anti-apoptosis, as well as polarizing M2 macrophage in vivo. Meanwhile, the in vitro results also showed that FNDC5-MSCs-Exo decreased pro-inflammatory secretion and increased anti-inflammatory secretion under LPS stimulation, which partly depressed NF‐κB signaling pathway and upregulated Nrf2/HO-1 Axis. Conclusions FNDC5-BMMSCs-derived exosomes play anti-inflammation effects and promote M2 macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis, which may develop a promising cell-free therapy for MI.


PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3000941
Author(s):  
Masum M. Mia ◽  
Dasan Mary Cibi ◽  
Siti Aishah Binte Abdul Ghani ◽  
Weihua Song ◽  
Nicole Tee ◽  
...  

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow–derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 (IL6) expression and impede reparative response by decreasing Arginase-I (Arg1) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.


2019 ◽  
Vol 22 (1) ◽  
pp. E019-E023 ◽  
Author(s):  
Yang Liu ◽  
Hongliang Wang ◽  
Xiudan Wang ◽  
Guohong Xie

Background: To study the effect of miR-29b on myocardial infarction via Notch signaling pathway in rats. Methods: The rat acute myocardial infarction (AMI) models were established and were divided into AMI group, sham group and normal group (N = 10 in each group). HE (Hemotoxylin and eosin) staining was used to detect whether the model was constructed successfully. MiR-29b mimics, inhibitors, mimics negative control (NC) were transfected into H9c2 (2-1) cells. Then, cells were divided into a mimics group, inhibitor group, NC group, and blank group. The relative expression levels of miR-29b, Notch1, DII4 and Hesl were detected by qRT-PCR. The expression of NICD1 was detected by Western blotting. Results: The rat AMI model was successfully constructed. Compared with normal and sham groups, the miR-29b expression was down-regulated, while the expression of Notch1, DII4 and Hesl was increased, and the NICD1 protein expression was increased in the myocardial infarction area of the AMI group (P < .05). Compared with the NC and blank groups, the relative expression of Notch1, DII4, Hesl and NICD1 were upregulated in the mimics group (P < .05), whereas the expression of Notch1, DII4, Hesl and NICD1 in the inhibitor group was decreased (P < .05). Conclusion: MiR-29b inhibited myocardial fibrosis and cardiac hypertrophy by activating the Notch signaling pathway and protected myocardium against myocardial infarction.


2020 ◽  
Vol 98 (6) ◽  
pp. 391-399
Author(s):  
Xiaojie Jiang ◽  
Xin Huang ◽  
Yifan Tong ◽  
Hong Gao

Increased inflammation is found in cardiac sympathetic neural remodeling with malignant ventricular arrhythmia (VA) following myocardial infarction (MI). Butyrate, as a microbiota-derived short-chain fatty acid, can inhibit inflammation and myocardial hypertrophy. However, the role of butyrate in sympathetic neural remodeling after MI is unknown. This study aimed to investigate whether butyrate could improve cardiac dysfunction and VA following MI by regulating inflammation and sympathetic neural remodeling. MI rats were randomized to administrate the butyrate or vehicle through intraperitoneal injection to undergo the study. Our data demonstrated that butyrate treatment preserved the partial cardiac function at 7 days post-MI. Butyrate downregulated the expression of essential for inflammatory response in the infarct border zone at 3 days post-MI. Particularly, butyrate promoted expression of M2 macrophage markers. Increased expressions of nerve growth factor and norephinephrine at 7 days after MI were inhibited in butyrate-treated rats. Furthermore, butyrate significantly decreased the density of nerve fibers for growth-associated protein-43 and tyrosine hydroxylase and resulted in fewer episodes of inducible VA. In conclusion, butyrate administration ameliorated cardiac function and VA after MI possibly through promoting M2 macrophage polarization to suppress inflammatory responses and inhibit sympathetic neural remodeling and may present an effective pharmacological strategy for the prevention of MI-related remodeling.


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