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Sirolimus-induced vascular dysfunction. Increased mitochondrial and nicotinamide adenosine dinucleotide phosphate

Alexander Jabs1, Sebastian Göbel, Philip Wenzel

  • 1II Medizinische Klinik für Kardiologie und Angiologie, Johannes Gutenberg University, Mainz, Germany.

Journal of the American College of Cardiology
|May 31, 2008
PubMed
Abstract

Insights

Sirolimus causes vascular dysfunction and nitrate resistance by increasing superoxide production from mitochondria and NADPH oxidase. This contributes to endothelial dysfunction after sirolimus-eluting stent use.

Area of Science:

  • Cardiovascular Research
  • Pharmacology
  • Biomedical Engineering

Background:

  • Sirolimus-eluting stents are effective against restenosis but can cause endothelial dysfunction.
  • Impaired re-endothelialization is a concern with sirolimus-eluting stents.

Purpose of the Study:

  • To investigate the mechanisms behind sirolimus-induced vascular dysfunction.
  • To analyze how sirolimus affects vascular endothelial function and vasoreactivity.

Main Methods:

  • Wistar rats received continuous sirolimus infusion for 7 days via osmotic pumps.
  • Assessed endothelial dysfunction, vasoreactivity to nitroglycerin, and superoxide production (dihydroethidine, L012).
  • Measured NADPH oxidase activity (p67(phox)/rac1 expression, rac1 association) and nitric oxide bioavailability (electron spin resonance, serum nitrite).

Main Results:

  • Sirolimus induced significant endothelial dysfunction and nitroglycerin resistance.
  • Elevated superoxide production was observed in aortae and heart mitochondria.
  • NADPH oxidase activity was upregulated, and nitric oxide bioavailability decreased by 40%.

Conclusions:

  • Continuous sirolimus treatment leads to vascular dysfunction and nitrate resistance.
  • Increased mitochondrial superoxide and NADPH oxidase activity contribute to sirolimus-induced vascular dysfunction.
  • These mechanisms may explain endothelial dysfunction associated with sirolimus-coated stents.

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