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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

Sirolimus-Induced Vascular Dysfunction

Increased Mitochondrial and Nicotinamide Adenosine Dinucleotide Phosphate Oxidase-Dependent Superoxide Production and Decreased Vascular Nitric Oxide Formation

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

Manuscript received October 11, 2007; revised manuscript received December 31, 2007, accepted January 21, 2008.

^_* Reprint requests and correspondence: Dr. Thomas Münzel, II Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (Email: tmuenzel{at}uni-mainz.de).

Objectives: 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.

Abbreviations and Acronyms   ACh = acetylcholine   CHD = coronary heart disease   DES = drug-eluting stent(s)   DHE = dihydroethidine   eNOS = endothelial nitric oxide synthase   FKBP12 = FK506 binding protein 12   L-NAME = NG-nitro-L-arginine methyl ester   mPTP = mitochondrial permeability transition pore   mTOR = mammalian target of rapamycin   NADPH = nicotinamide adenosine dinucleotide phosphate   NO = nitric oxide   NOS = nitric oxide synthase   NTG = nitroglycerin   PKC = protein kinase C   PMA = phorbol myristate   qRT-PCR = real-time quantitative reverse-transcriptase polymerase chain reaction   ROS = reactive oxygen species

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