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Published on: June 3, 2018
Exosomal miR-376c-3p derived from cardiac fibroblasts triggers cardiac hypertrophy by targeting ERP44
Yuexin Zhang1, Xiaopei Hu1, Jie Li1
1School of Pharmaceutical Sciences, Sun Yat-Sen University, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, China.
Insights
Cardiac fibroblasts release exosomes containing microRNA-376c-3p, promoting cardiac hypertrophy by affecting calcium signaling. Targeting this exosomal microRNA offers a potential therapeutic strategy for heart conditions.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Exosomes mediate intercellular communication and are implicated in cardiac abnormalities like hypertrophy.
- Cardiac fibroblasts (CFs) secrete exosomes (CFs-Exo) involved in myocardial ischemia and atrial fibrillation.
- The specific role of CFs-Exo in cardiac hypertrophy and its mechanism remain unclear.
Purpose of the Study:
- To investigate the role of CFs-Exo in cardiac hypertrophy.
- To elucidate the underlying molecular mechanism involving microRNA-376c-3p (miR-376c-3p).
Main Methods:
- Stimulation of CFs with isoproterenol (ISO) and analysis of secreted exosomes.
- Treatment of neonatal rat cardiomyocytes (CMs) with CFs-Exo.
- Identification of miR-376c-3p targets using bioinformatics and experimental validation.
- In vivo studies in mice using miR-376c-3p mimics or downregulation in CFs-Exo.
Main Results:
- ISO-stimulated CFs-Exo induced hypertrophic responses and activated calcium signaling in CMs.
- miR-376c-3p expression and content increased in ISO-stimulated CFs and their exosomes.
- Exosomal miR-376c-3p suppressed endoplasmic reticulum protein 44, promoting Ca2+ release and activating calcineurin/NFAT signaling, leading to hypertrophy.
- In vivo administration of miR-376c-3p-enriched exosomes caused cardiac hypertrophy and impaired heart function in mice.
Conclusions:
- CFs-Exo, particularly via exosomal miR-376c-3p, play a significant role in the pathogenesis of cardiac hypertrophy.
- miR-376c-3p acts by inhibiting endoplasmic reticulum protein 44, disrupting calcium homeostasis and activating hypertrophic signaling pathways.
- Intervention targeting exosomal miR-376c-3p presents a potential therapeutic strategy for pathological cardiac hypertrophy.
Abstract:
Recent studies have revealed that exosomes, important regulators of intercellular communication, participate in various cardiac abnormalities, including hypertrophy. Cardiac fibroblasts (CFs) are one of the most abundant cell types of the heart. Exosomes secreted by CFs (CFs-Exo) have been proven to participate in myocardial ischemia and atrial fibrillation. However, the roles of CFs-Exo in cardiac hypertrophy and the underlying mechanism remain to be elucidated. Our study revealed that exosomes from isoproterenol (ISO)-stimulated CFs induced hypertrophic responses and activated the calcium signaling pathway in neonatal rat cardiomyocytes (CMs). The expression of microRNA-376c-3p (miR-376c-3p) was significantly increased in CFs following ISO stimulation; concomitantly, the contents of miR-376c-3p were also increased in their exosomes. The pro-hypertrophic effects of ISO-stimulated CFs could be attributed to the exosomal delivery of miR-376c-3p, which was subsequently absorbed by neonatal rat CMs and resulted in elevated cellular miR-376c-3p content. Furthermore, endoplasmic reticulum protein 44 was identified as a direct target of miR-376c-3p. MiR-376c-3p suppressed endoplasmic reticulum protein 44 in CMs to promote Ca2+ release from the sarcoplasmic reticulum, leading to the activation of calcineurin/nuclear factors of activated T cells signaling and the subsequent onset of hypertrophy. Additionally, transfection of CFs with miR-376c-3p mimic upregulated miR-376c-3p in the derived exosomes. Administration of mimic upregulated miR-376c-3p in the derived exosomes provoked cardiac hypertrophy and impaired heart function in mice. In contrast, downregulation of miR-376c-3p in exosomes of CFs ameliorated the detrimental effects of exosomes on CMs. These results uncovered a new role of CFs-Exo in the pathogenesis of cardiac hypertrophy, suggesting a potential therapeutic strategy by counteracting exosomal miR-376c-3p. SIGNIFICANCE STATEMENT: Our data showed that the microRNA-376c-3p (miR-376c-3p) level was increased in isoproterenol-activated fibroblasts and secreted exosomes, which subsequently provoked hypertrophic responses via promoting Ca2+ release from the sarcoplasmic reticulum in cardiomyocytes. The detrimental effects of miR-376c-3p could be attributed to the inhibition of the downstream target endoplasmic reticulum protein 44. These findings highlighted a novel mechanism of exosome-mediated pathological cardiac hypertrophy and suggested a promising therapeutic strategy by intervening in exosomal miR-376c-3p.