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Published on: July 30, 2018
Rosmarinic Acid-Treated Exosomes Modulate TGF-β1/Smad3 Signaling to Alleviate Cardiac Fibrosis in an In Vitro/In Vivo
Zahra Mansouri1, Mahin Dianat1, Mohammad Badavi1
1Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, and Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Insights
Rosmarinic acid-primed exosomes effectively combat cardiac fibrosis after myocardial injury. This novel therapy improves heart function by reducing oxidative stress and collagen deposition, offering a promising treatment for heart failure.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Stem Cell Therapy
Background:
- Cardiac fibrosis (CF) is a significant complication of myocardial infarction (MI), leading to impaired heart function and heart failure.
- Rosmarinic acid (RA) demonstrates cardioprotective and antifibrotic effects, making it a potential therapeutic agent for CF.
- Exosomes derived from adipose-derived stem cells (ADSCs) show therapeutic potential, but their efficacy can be enhanced.
Purpose of the Study:
- To evaluate the efficacy of exosomes derived from RA-primed ADSCs (RA-MSC-Exo) in mitigating cardiac fibrosis.
- To investigate how RA-priming enhances the antioxidant and antifibrotic capacity of ADSC-derived exosomes.
- To assess the therapeutic potential of RA-MSC-Exo in an Isoproterenol (ISO)-induced myocardial injury model.
Main Methods:
- Established an in vitro (H9C2 cardiomyoblasts) and in vivo (Wistar rats) ISO-induced myocardial injury model.
- Treated cells and rats with exosomes (Exo) or RA-primed exosomes (RA-MSC-Exo).
- Assessed cell viability, apoptosis, cardiac biomarkers, oxidative stress (ROS, TAC), cardiac function (echocardiography), fibrosis signaling pathways (NF-κB, TGF-β1, Smad3), and collagen deposition (histology).
Main Results:
- Both Exo and RA-MSC-Exo treatments improved cell viability and reduced apoptosis in vitro.
- In vivo, both treatments significantly reduced cardiac biomarkers, decreased ROS, and enhanced TAC levels.
- RA-MSC-Exo and Exo interventions downregulated NF-κB, TGF-β1, Smad3, and Collagen I, attenuated collagen deposition, and improved cardiac function.
Conclusions:
- RA-primed exosomes effectively mitigate cardiac fibrosis and improve cardiac function in a myocardial ischemia model.
- RA-priming enhances the antioxidant and antifibrotic properties of ADSC-derived exosomes.
- This targeted exosome therapy presents a promising strategy for managing myocardial injury and preventing heart failure.
Abstract:
Cardiac fibrosis (CF) is a major complication of myocardial infarction (MI), impairing myocardial function and leading to heart failure. Rosmarinic acid (RA) exhibits cardioprotective and antifibrotic properties, representing a promising therapeutic strategy for CF. This study evaluated the efficacy of exosomes derived from RA-primed adipose-derived stem cells (ADSCs), focusing on how RA-priming enhances their antioxidant and antifibrotic capacity against CF. An Isoproterenol (ISO)-induced myocardial injury model was established in vitro and in vivo. In vitro, H9C2 cardiomyoblasts were first injured with ISO and then treated with either exosomes (Exo) or RA-primed exosomes (RA-MSC-Exo) to assess cell viability and apoptosis. In vivo, 48 Wistar rats were divided into six groups: Control, Exo, RA-MSC-Exo, ISO, ISO + Exo, and ISO + RA-MSC-Exo. We assessed cardiac biomarkers (CK-MB and troponin I), reactive oxygen species (ROS), and total antioxidant capacity (TAC). We performed echocardiographic, molecular (real-time PCR and Western blotting), and histological analyses (Masson's trichrome staining) to evaluate cardiac function, fibrosis signaling pathways (NF-κB, TGF-β1, SMAD3), and collagen deposition. In vitro, both Exo and RA-MSC-Exo treatments significantly restored cell viability and reduced apoptosis in ISO-injured H9C2 cells. In vivo, both treatments significantly mitigated ISO-induced cardiac injury by reducing cardiac biomarkers, decreasing ROS production, and enhancing TAC levels. These interventions downregulated the expression of NF-κB, TGF-β1, Smad3, and Collagen I, leading to attenuated collagen deposition and improved cardiac function. Our study demonstrates that RA-primed exosomes effectively mitigate CF and improve cardiac function in an ISO-induced myocardial ischemia model. This targeted approach offers a promising therapeutic strategy for managing myocardial injury and its fibrotic complications.
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