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Sivelestat Alleviates Atherosclerosis by Improving Intestinal Barrier Function and Reducing Endotoxemia.

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Sivelestat, a neutrophil elastase inhibitor, reduces atherosclerosis by improving gut barrier function and decreasing inflammation. This study highlights the gut-vascular axis in cardiovascular disease development and treatment.

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Area of Science:

  • Cardiovascular Science
  • Immunology
  • Gastroenterology

Background:

  • Atherosclerosis is a chronic inflammatory disease where immune cells drive vascular inflammation and plaque formation.
  • Gastrointestinal disorders are increasingly recognized as contributing factors to atherosclerosis.
  • Neutrophil elastase plays a role in intestinal inflammation during atherosclerosis.

Purpose of the Study:

  • To investigate the therapeutic effects of sivelestat, a neutrophil elastase inhibitor, on atherosclerosis.
  • To explore the interaction between gastrointestinal health and the progression of atherosclerosis.
  • To elucidate the mechanisms underlying sivelestat's protective effects.

Main Methods:

  • Utilized Western diet-fed ApoE-/- mice to model atherosclerosis.
  • Administered sivelestat and assessed atherosclerotic phenotypes, lipid accumulation, and inflammatory markers.
  • Investigated intestinal permeability, endotoxemia, and the expression of key proteins like zonula occludens-1.
  • Conducted a clinical correlation study linking endotoxin levels and neutrophil elastase activity to carotid intima-medial thickness.

Main Results:

  • Sivelestat treatment attenuated atherosclerotic phenotypes, reducing lipid deposition and monocyte infiltration.
  • Sivelestat decreased intestinal permeability and endotoxemia in atherosclerotic mice.
  • Sivelestat upregulated zonula occludens-1 expression and suppressed intestinal inflammation and NF-κB activity.
  • Lipopolysaccharide administration negated sivelestat's anti-atherosclerotic benefits, confirming the role of endotoxemia.
  • Clinical data showed positive correlations between endotoxin levels, neutrophil elastase activity, and carotid intima-medial thickness.

Conclusions:

  • Sivelestat demonstrates significant pharmacological benefits in protecting against atherosclerosis.
  • Maintaining intestinal homeostasis is crucial in mitigating atherosclerotic development.
  • Targeting neutrophil elastase and addressing gut-vascular interactions offers a potential therapeutic strategy for atherosclerosis.