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.

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