Dataset Information

Exosomes Derived From Hypertrophic Cardiomyocytes Induce Inflammation in Macrophages via miR-155 Mediated MAPK Pathway.

ABSTRACT: The inflammatory immune microenvironment plays an important role in the development of cardiac hypertrophy. Exosomes have emerged as the potent modulators of inflammatory responses. This study aimed to determine how exosomes derived from angiotensin II (Ang II)-induced hypertrophic cardiomyocytes (HCs) interfere with the inflammatory signal pathways in macrophages. Herein, we showed that increased exosome release was observed in HCs when compared to normal cardiomyocytes (NCs). Incubation of the murine macrophage cell line RAW264.7 in the presence of exosomes isolated from the culture media of HCs triggers the secretion of inflammatory cytokines interleukin (IL)-6 and IL-8. Cytokines release induced by HCs-derived exosomes was prevented by down-regulation of Argonaute2 (AGO2), suggesting that the non-coding RNAs were involved in exosome-induced inflammatory responses in RAW 264.7 macrophages. RNA sequencing assays further demonstrated that a total of seven microRNAs were differentially expressed between NCs-derived and HCs-derived exosomes. Importantly, miR-155 played a crucial role in the initiation of inflammation in macrophages. Further analyses demonstrated that HCs-derived exosomes induced the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 via miR-155. Our results support the concept that exosomal microRNAs have emerged as important inflammatory response modulators regulating cardiac hypertrophy.

SUBMITTER: Yu H

PROVIDER: S-EPMC7886800 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Exosomes Derived From Hypertrophic Cardiomyocytes Induce Inflammation in Macrophages <i>via</i> miR-155 Mediated MAPK Pathway.

Yu Hui H Qin Lei L Peng Yunzhi Y Bai Wenhui W Wang Zhanli Z

Frontiers in immunology 20210203

The inflammatory immune microenvironment plays an important role in the development of cardiac hypertrophy. Exosomes have emerged as the potent modulators of inflammatory responses. This study aimed to determine how exosomes derived from angiotensin II (Ang II)-induced hypertrophic cardiomyocytes (HCs) interfere with the inflammatory signal pathways in macrophages. Herein, we showed that increased exosome release was observed in HCs when compared to normal cardiomyocytes (NCs). Incubation of the ...[more]

PMID: 33613526

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Project description:Cardiac progenitor cells derived from adult heart have emerged as one of the most promising stem cell types for cardiac protection and repair. Exosomes are known to mediate cell-cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we investigated the cardiac progenitor cell (CPC)-derived exosomal miRNAs on protecting myocardium under oxidative stress. Sca1(+)CPCs-derived exosomes were purified from conditional medium, and identified by nanoparticle trafficking analysis (NTA), transmission electron microscopy and western blotting using CD63, CD9 and Alix as markers. Exosomes production was measured by NTA, the result showed that oxidative stress-induced CPCs secrete more exosomes compared with normal condition. Although six apoptosis-related miRNAs could be detected in two different treatment-derived exosomes, only miR-21 was significantly upregulated in oxidative stress-induced exosomes compared with normal exosomes. The same oxidative stress could cause low miR-21 and high cleaved caspase-3 expression in H9C2 cardiac cells. But the cleaved caspase-3 was significantly decreased when miR-21 was overexpressed by transfecting miR-21 mimic. Furthermore, miR-21 mimic or inhibitor transfection and luciferase activity assay confirmed that programmed cell death 4 (PDCD4) was a target gene of miR-21, and miR-21/PDCD4 axis has an important role in anti-apoptotic effect of H9C2 cell. Western blotting and Annexin V/PI results demonstrated that exosomes pre-treated H9C2 exhibited increased miR-21 whereas decreased PDCD4, and had more resistant potential to the apoptosis induced by the oxidative stress, compared with non-treated cells. These findings revealed that CPC-derived exosomal miR-21 had an inhibiting role in the apoptosis pathway through downregulating PDCD4. Restored miR-21/PDCD4 pathway using CPC-derived exosomes could protect myocardial cells against oxidative stress-related apoptosis. Therefore, exosomes could be used as a new therapeutic vehicle for ischemic cardiac disease.

Project description:BACKGROUND:How exosomal microRNAs (miRNAs) derived from macrophages contribute to the development of drug resistance in the context of the hypoxic tumor microenvironment in epithelial ovarian cancer (EOC) remains poorly understood. METHODS:The miRNA levels were detected by qRT-PCR. Protein levels of HIF-1α, CD163 and PTEN-PI3K/AKT pathway were assessed by Western blot (WB) and Immunohistochemistry (IHC). Exosomes were isolated, and then confirmed by Transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA) and WB. Internalization of macrophages-secreted exosomes in EOC cells was detected by Confocal microscope. Subsequently, Dual-luciferase reporter assay verified PTEN was the target of miR-223. Gain- and loss-of-function experiments, rescue experiments, and SKOV3 xenograft models were performed to uncover the underlying mechanisms of miR-223 and PTEN-PI3K/AKT pathway, as well as the exosomal miR-223 in inducing multidrug resistance in vitro and in vivo. RESULTS:Here, we showed hypoxic EOC cells triggered macrophages recruitment and induced macrophages into a tumor-associated macrophage (TAM)-like phenotype; exosomes derived from hypoxic macrophages enhanced the malignant phenotype of EOC cells, miR-223 was enriched in exosomes released from macrophages under hypoxia, which could be transferred to the co-cultivated EOC cells, accompanied by enhanced drug resistant of EOC cells. Besides, results from a functional assay revealed that exosomal miR-223 derived from macrophages promoted the drug resistance of EOC cells via the PTEN-PI3K/AKT pathway both in vivo and in vitro. Furthermore, patients with high HIF-1a expression had statistically higher CD163+ cell infiltration and intertumoral levels of miR-223. Finally, circulating exosomal miR-223 levels were closely related to the recurrence of EOC. CONCLUSIONS:These data indicate a unique role of exosomal miR-223 in the cross-talk between macrophages and EOC cells in chemotherapy resistance, through a novel exosomal miR-223/PTEN-PI3K/AKT signaling pathway.

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Exosomes Derived From Hypertrophic Cardiomyocytes Induce Inflammation in Macrophages via miR-155 Mediated MAPK Pathway.

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Exosomes Derived From Hypertrophic Cardiomyocytes Induce Inflammation in Macrophages <i>via</i> miR-155 Mediated MAPK Pathway.

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