Sirolimus-induced vascular dysfunction. Increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation.
OBJECTIVE
This study sought to analyze mechanisms that mediate vascular dysfunction induced by sirolimus.


BACKGROUND
Despite excellent antirestenotic capacity, sirolimus-eluting stents have been found to trigger coronary endothelial dysfunction and impaired re-endothelialization.


METHODS
To mimic the continuous sirolimus exposure of a stented vessel, Wistar rats underwent drug infusion with an osmotic pump for 7 days.


RESULTS
Sirolimus treatment caused a marked degree of endothelial dysfunction as well as a desensitization of the vasculature to the endothelium-independent vasodilator nitroglycerin. Also, sirolimus stimulated intense transmural superoxide formation as detected by dihydroethidine fluorescence in aortae. Increased superoxide production was mediated in part by the vascular nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase as indicated by a marked stimulation of p67(phox)/rac1 NADPH oxidase subunit expression and by increased rac1 membrane association. In addition, superoxide production in rat heart mitochondria was up-regulated by sirolimus, as measured by L012-enhanced chemiluminescence. As a consequence, electron spin resonance measurements showed a 40% reduction in vascular nitric oxide bioavailability, which was further supported by decreased serum nitrite levels.


CONCLUSIONS
Sirolimus causes marked vascular dysfunction and nitrate resistance after continuous treatment for 7 days. This impaired vasorelaxation may, in part, be induced by up-regulated mitochondrial superoxide release as well as by an up-regulation of NADPH oxidase-driven superoxide production. Both processes could contribute to endothelial dysfunction observed after coronary vascular interventions with sirolimus-coated stents.
II Medizinische Klinik für Kardiologie und Angiologie, Johannes Gutenberg University, Mainz, Germany.
Alexander
A
Jabs
Sebastian
S
Göbel
Philip
P
Wenzel
Andrei L
AL
Kleschyov
Marcus
M
Hortmann
Matthias
M
Oelze
Andreas
A
Daiber
Thomas
T
Münzel
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D045462:Endothelium-Dependent Relaxing Factors; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects*; D023421:Models, Animal; D019255:NADPH Oxidases / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D045462:Endothelium-Dependent Relaxing Factors; D007166:Immunosuppressive Agents; D013481:Superoxides; D009569:Nitric Oxide; D019255:NADPH Oxidases; D020123:Sirolimus