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Exosomal miR-15a-5p from cardiomyocytes promotes myocardial fibrosis
Feng Cao1,2,3, Zhe Li4,5,6, Wenmao Ding4,5,6
1Department of Cardiology, Renmin Hospital of Wuhan University, NO.99 Zhangzhidong Road, Wuchang District, Wuhan, 430060, China. fengcao213@163.com.
Abstract:
The emergence of myofibroblasts is a key step in myocardial fibrosis, but the trigger for the transformation of cardiac fibroblasts into myofibroblasts remains not entirely clear. Exosomes play a key role between cardiomyocytes and cardiac fibroblasts. Here, we not only investigated the relationship between exosomes derived from angiotensin (Ang)-II-treated cardiomyocytes and cardiac fibroblasts, the underlying mechanisms were also explored. Ang-II-treated C57 male mice and mouse cardiac fibroblasts were employed for in vivo and in vitro experiments, respectively. Transmission electron microscopy nanoparticle tracking analysis, and western blot of CD9, CD63, CD81 were performed to identify exosomes; QRT-PCR was performed to detect miR-15a-5p expression; luciferase reporter assay was employed to determine the interaction between miR-15a-5p and dyrk2; western blot was performed to examine the protein levels of fibrosis markers; Counting Kit-8 was performed to determine cell viability; HE and Masson staining were performed to assess the pathological changes of myocardial tissues. MiR-15a-5p expression was found up-regulated in serum of myocardial fibrosis patients, serum and myocardial tissues of Ang-II-treated mice, and Ang-II-treated cardiomyocytes. Mechanically, exosomes from Ang-II-treated cardiomyocytes shuttled miR-15a-5p to cardiac fibroblasts, where miR-15a-5p dephosphorylated NFAT by targeting dyrk2 to promote cell viability and elevated the protein levels of α-smooth muscle actin, collagen type 1 α1 and collagen type 3 α1, thus promoting myocardial fibrosis. This study identified a novel molecular target for anti-fibrotic therapeutic interventions.
Insights
Cardiomyocyte exosomes deliver miR-15a-5p to cardiac fibroblasts, promoting myocardial fibrosis by targeting dyrk2. This uncovers a new target for anti-fibrotic therapies.
Area of Science:
- Cardiovascular Biology
- Cell Biology
- Molecular Medicine
Background:
- Myofibroblast activation is central to myocardial fibrosis.
- The precise triggers for cardiac fibroblast to myofibroblast differentiation are not fully understood.
- Exosomes mediate intercellular communication between cardiomyocytes and cardiac fibroblasts.
Purpose of the Study:
- To investigate the role of exosomes from angiotensin (Ang)-II-treated cardiomyocytes in cardiac fibroblast activation.
- To elucidate the molecular mechanisms by which these exosomes influence myocardial fibrosis.
- To identify potential therapeutic targets for anti-fibrotic interventions.
Main Methods:
- In vivo (Ang-II-treated mice) and in vitro (mouse cardiac fibroblasts) models were used.
- Exosome characterization involved transmission electron microscopy, nanoparticle tracking analysis, and western blotting for exosomal markers (CD9, CD63, CD81).
- MiR-15a-5p expression, exosome-fibroblast interaction, target engagement (dyrk2), fibrosis markers, cell viability, and myocardial pathology were assessed using QRT-PCR, luciferase assays, western blotting, CCK-8, HE, and Masson staining.
Main Results:
- Exosomes derived from Ang-II-treated cardiomyocytes were identified and characterized.
- MiR-15a-5p expression was upregulated in myocardial fibrosis patients, Ang-II-treated mice, and Ang-II-treated cardiomyocytes.
- Exosomes transported miR-15a-5p to cardiac fibroblasts, leading to dyrk2 targeting, NFAT dephosphorylation, increased cell viability, and elevated expression of fibrosis markers (α-SMA, COL1A1, COL3A1), ultimately promoting myocardial fibrosis.
Conclusions:
- Exosomes from Ang-II-stimulated cardiomyocytes promote myocardial fibrosis via miR-15a-5p transfer to cardiac fibroblasts.
- The mechanism involves targeting dyrk2, dephosphorylating NFAT, and upregulating fibrosis-associated proteins.
- This pathway presents a novel molecular target for developing anti-fibrotic therapies.
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