Exosome in Cardiovascular Diseases: A Complex World Full of Hope

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Abstract

Exosomes are a subgroup of extracellular vesicles containing a huge number of bioactive molecules. They represent an important means of cell communication, mostly between different cell populations, with the purpose of maintaining tissue homeostasis and coordinating the adaptive response to stress. This type of intercellular communication is important in the cardiovascular field, mainly due to the fact that the heart is a complex multicellular system. Given the growing interest in the role of exosomes in cardiovascular diseases and the numerous studies published in the last few decades, we focused on the most relevant results about exosomes in the cardiovascular filed starting from their characterization, passing through the study of their function, and ending with perspectives for their use in cardiovascular therapies.

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Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells.

Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot … (2010)

Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.

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Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4

J. Xiao, Y. Y. Pan, X. Li … (2016)

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.

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MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy.

Ngoc-Quynh-Nhu Nguyen, Sebastien P Tabruyn, Marc Thiry … (2013)

Peripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy in previously healthy women. Although PPCM is driven in part by the 16-kDa N-terminal prolactin fragment (16K PRL), the underlying molecular mechanisms are poorly understood. We found that 16K PRL induced microRNA-146a (miR-146a) expression in ECs, which attenuated angiogenesis through downregulation of NRAS. 16K PRL stimulated the release of miR-146a-loaded exosomes from ECs. The exosomes were absorbed by cardiomyocytes, increasing miR-146a levels, which resulted in a subsequent decrease in metabolic activity and decreased expression of Erbb4, Notch1, and Irak1. Mice with cardiomyocyte-restricted Stat3 knockout (CKO mice) exhibited a PPCM-like phenotype and displayed increased cardiac miR-146a expression with coincident downregulation of Erbb4, Nras, Notch1, and Irak1. Blocking miR-146a with locked nucleic acids or antago-miRs attenuated PPCM in CKO mice without interrupting full-length prolactin signaling, as indicated by normal nursing activities. Finally, miR-146a was elevated in the plasma and hearts of PPCM patients, but not in patients with dilated cardiomyopathy. These results demonstrate that miR-146a is a downstream-mediator of 16K PRL that could potentially serve as a biomarker and therapeutic target for PPCM.

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Journal

Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 17 February 2019

Publication date Collection: February 2019

Volume: 8

Issue: 2

Electronic Location Identifier: 166

Affiliations

[1 ]Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy; gloria.bellin@ 123456gmail.com (G.B.); chiara.gardin@ 123456unipd.it (C.G.); letizia.ferroni@ 123456unipd.it (L.F.)

[2 ]Maria Pia Hospital, GVM Care & Research, 10132 Torino, Italy

[3 ]Laboratory of Biosurgical Research (Alain Carpentier Foundation), Pompidu Hospital, University Paris Descartes, 75015 Paris, France; j.chachques-ext@ 123456aphp.fr

[4 ]Rogante Engineering Office, 62012 Civitanova Marche, Italy; main@ 123456roganteengineering.it

[5 ]Laboratory for Stem Cells, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia; dinko.mitrecic@ 123456mef.hr

[6 ]Maria Cecilia Hospital, GVM Care & Research, 48033 Ravenna, Italy; fri@ 123456unife.it

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[* ]Correspondence: barbara.zavan@ 123456unipd.it ; Tel.: +39-049-827-6096

Author information

Gloria Bellin https://orcid.org/0000-0001-7932-3205

Massimo Rogante https://orcid.org/0000-0002-6846-0826

Barbara Zavan https://orcid.org/0000-0002-4779-4456

Article

Publisher ID: cells-08-00166

DOI: 10.3390/cells8020166

PMC ID: 6406975

PubMed ID: 30781555

SO-VID: 012f7b1e-e313-487e-9192-d19894ff35a4

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Exosome in Cardiovascular Diseases: A Complex World Full of Hope

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Journal of Circulating Biomarkers

Most cited references 31

Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells.

Cardiac progenitor cell-derived exosomes prevent cardiomyocytes apoptosis through exosomal miR-21 by targeting PDCD4

MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy.

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