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Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro.

ABSTRACT: Despite the widespread clinical use of cardioprotection by long-term direct antagonism of P2Y12 receptor, underlying mechanisms are unclear. Here, we identify how release of pro-survival exosomes from human cardiac-derived mesenchymal progenitor cells (hCPCs) is regulated by clinically relevant dose of ticagrelor (1??M), an oral selective and reversible non-thienopyridine P2Y12 inhibitor. Ticagrelor-induced enhancement of exosome levels is related to increased mitotic activity of hCPCs. We show a drug-response threshold above which the effects on hCPCs are lost due to higher dose of ticagrelor and larger adenosine levels. While it is known that pan-Aurora kinase inhibitor halts cell proliferation through dephosphorylation of histone H3 residue Ser10, we demonstrate that it also prevents ticagrelor-induced effects on release of cardiac progenitor cell-derived exosomes delivering anti-apoptotic HSP70. Indeed, sustained pre-treatment of cardiomyocytes with exosomes released from explant-derived hCPCs exposed to low-dose ticagrelor attenuated hypoxia-induced apoptosis through acute phosphorylation of ERK42/44. Our data indicate that ticagrelor can be leveraged to modulate release of anti-hypoxic exosomes from resident hCPCs.

SUBMITTER: Casieri V

PROVIDER: S-EPMC7016113 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro.

Casieri Valentina V Matteucci Marco M Pasanisi Emilio M EM Papa Angela A Barile Lucio L Fritsche-Danielson Regina R Lionetti Vincenzo V

Scientific reports 20200212 1

Despite the widespread clinical use of cardioprotection by long-term direct antagonism of P2Y12 receptor, underlying mechanisms are unclear. Here, we identify how release of pro-survival exosomes from human cardiac-derived mesenchymal progenitor cells (hCPCs) is regulated by clinically relevant dose of ticagrelor (1 μM), an oral selective and reversible non-thienopyridine P2Y<sub>12</sub> inhibitor. Ticagrelor-induced enhancement of exosome levels is related to increased mitotic activity of hCPC ...[more]

PMID: 32051439

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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.

Dataset Information

Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro.

Publications

Ticagrelor Enhances Release of Anti-Hypoxic Cardiac Progenitor Cell-Derived Exosomes Through Increasing Cell Proliferation In Vitro.

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