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Myofibroblast-Derived Exosome Induce Cardiac Endothelial Cell Dysfunction
Prabhat Ranjan1, Rajesh Kumari1, Sumanta Kumar Goswami1
1Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States.
Insights
Activated fibroblast exosomes carrying miR-200a-3p impair endothelial cell function. Inhibiting this microRNA in fibroblasts improved endothelial cell biology and vascular homeostasis, highlighting a novel therapeutic target.
Area of Science:
- Cardiovascular Biology
- Cell Biology
- Extracellular Vesicles
Background:
- Endothelial cells (ECs) are crucial for vascular homeostasis and heart function.
- The impact of fibroblast-derived exosomes on ECs remains unclear, despite their known effects on cardiomyocytes.
- This study investigates the role of activated cardiac fibroblast-derived exosomes (FB-Exo) in EC dysfunction.
Purpose of the Study:
- To determine if activated cardiac FB-Exo mediate EC dysfunction.
- To explore whether modulating FB-exosomal contents can improve endothelial function.
- To identify specific exosomal components responsible for EC dysfunction.
Main Methods:
- Exosomes were isolated from cardiac fibroblasts (FB) and characterized.
- ECs were treated with exosomes from TGF-β1-activated FBs (TGF-β1-FB-Exo) or control FBs.
- Gene expression, protein phosphorylation, cell proliferation, apoptosis, tube formation, and migration assays were performed.
Main Results:
- TGF-β1 activated FBs, evidenced by increased collagen and fibronectin expression.
- TGF-β1-FB-Exo treatment impaired EC function, reducing tube formation, migration, proliferation, and increasing apoptosis.
- Exosomes from activated FBs showed increased levels of fibrosis-associated microRNAs, notably miR-200a-3p.
- Inhibition of miR-200a-3p in activated FBs ameliorated EC dysfunction.
Conclusions:
- Activated fibroblast-derived exosomes play a significant role in endothelial cell dysfunction.
- miR-200a-3p within these exosomes is a key mediator of endothelial cell biology and function.
- Targeting exosomal miR-200a-3p presents a potential therapeutic strategy for vascular dysfunction.
Abstract:
Background: Endothelial cells (ECs) play a critical role in the maintenance of vascular homeostasis and in heart function. It was shown that activated fibroblast-derived exosomes impair cardiomyocyte function in hypertrophic heart, but their effect on ECs is not yet clear. Thus, we hypothesized that activated cardiac fibroblast-derived exosomes (FB-Exo) mediate EC dysfunction, and therefore modulation of FB-exosomal contents may improve endothelial function. Methods and Results: Exosomes were isolated from cardiac fibroblast (FB)-conditioned media and characterized by nanoparticle tracking analysis and electron microscopy. ECs were isolated from mouse heart. ECs were treated with exosomes isolated from FB-conditioned media, following FB culture with TGF-β1 (TGF-β1-FB-Exo) or PBS (control) treatment. TGF-β1 significantly activated fibroblasts as shown by increase in collagen type1 α1 (COL1α1), periostin (POSTN), and fibronectin (FN1) gene expression and increase in Smad2/3 and p38 phosphorylation. Impaired endothelial cell function (as characterized by a decrease in tube formation and cell migration along with reduced VEGF-A, Hif1α, CD31, and angiopoietin1 gene expression) was observed in TGF-β1-FB-Exo treated cells. Furthermore, TGF-β1-FB-Exo treated ECs showed reduced cell proliferation and increased apoptosis as compared to control cells. TGF-β1-FB-Exo cargo analysis revealed an alteration in fibrosis-associated miRNAs, including a significant increase in miR-200a-3p level. Interestingly, miR-200a-3p inhibition in activated FBs, alleviated TGF-β1-FB-Exo-mediated endothelial dysfunction. Conclusions: Taken together, this study demonstrates an important role of miR-200a-3p enriched within activated fibroblast-derived exosomes on endothelial cell biology and function.
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