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Inflammatory extracellular vesicles prompt heart dysfunction via TRL4-dependent NF-κB activation

Vanessa Biemmi1,2, Giuseppina Milano3,4, Alessandra Ciullo3

  • 1Laboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano, Switzerland.

Theranostics
|March 21, 2020
PubMed

Insights

Targeting extracellular vesicles after myocardial infarction preserves heart function. Reducing inflammatory vesicles early post-ischemia improved cardiac outcomes and reduced cardiomyocyte death.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Cell Biology

Background:

  • Myocardial infarction (MI) triggers inflammation and cardiac remodeling via damage-associated proteins and macrophage infiltration.
  • Circulating inflammatory extracellular vesicles (EVs) are key mediators in the progression of ischemia-induced inflammation.
  • This study investigates the hypothesis that EVs exert direct cytotoxicity on cardiomyocytes.

Purpose of the Study:

  • To determine if inhibiting inflammatory EV generation in early ischemia ameliorates cardiac outcomes.
  • To evaluate the cytotoxic effects of EVs on cardiomyocytes both in vivo and in vitro.
  • To elucidate the mechanisms by which inflammatory EVs induce cardiomyocyte death.

Main Methods:

  • Rats with induced myocardial infarction were treated with an extracellular vesicle biogenesis inhibitor.
  • Cardiac function was assessed using echocardiography and hemodynamic analysis.
  • Ex vivo and in vitro experiments evaluated the cytotoxic effects of circulating EVs on cardiomyocytes, including NF-κB pathway analysis.

Main Results:

  • Post-MI, circulating EVs increased significantly, carrying inflammatory alarmins.
  • Inhibition of inflammatory EVs preserved left ventricular ejection fraction and improved cardiac contractility and relaxation.
  • Post-infarction EVs induced greater cardiomyocyte death ex vivo compared to EVs from healthy rats, mediated by NF-κB nuclear translocation.

Conclusions:

  • Circulating inflammatory EVs contribute to cardiomyocyte cytotoxicity after myocardial infarction.
  • Targeting extracellular vesicles in the acute phase of MI shows therapeutic potential for preserving cardiac function.
  • Inhibiting EV biogenesis may represent a novel strategy to mitigate ischemia-reperfusion injury.

Keywords:
TLR4 axisinflammatory extracellular vesiclesmacrophagesmyocardial infarction

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