Roflumilast-induced Local Vascular Injury Is Associated with a Coordinated Proteome and Microparticle Change in the Systemic Circulation in Pigs. (June 2015)

• Record Type: Journal Article
• Authors: Vilahur, Gemma; Cubedo, Judit; Padró, Teresa; Casaní, Laura; Juan-Babot, Oriol; Crespo, Javier; Bendjama, Kaidre; Lawton, Michael; Badimon, Lina
• Is Part Of: Toxicologic pathology. Volume 43:Number 4(2015)
• Page Start: 569
• Page End: 580
• Publication Date: 2015-06
• Subjects: Roflumilast -- drug-induced vascular injury -- biomarkers -- proteomics; Pathology -- Periodicals; Toxicology -- Periodicals; Pathology; Toxicology; 615.9
• DOI: 10.1177/0192623314551971
• Languages: English
• ISSNs: 0192-6233

Abstract

Drug-induced vascular injury (DIVI) is commonly associated with phosphodiesterase (PDE) inhibitors. Despite histological characterization, qualified biomarkers for DIVI detection are lacking. We investigated whether a single administration of roflumilast (PDE-IV inhibitor) induces vascular damage and identified novel surrogate biomarkers of acute vascular injury. Pigs received postoperative 250, 375, or 500 μg of roflumilast or placebo/control. After 1.5 hr, coronary reactivity was determined by catheter-based administration of acetylcholine and sodium nitroprusside (SNP) in the coronary sinus. Immunohistochemical analysis of vessel integrity (von Willebrand factor [vWF]) and fibrin(ogen) deposition was performed in the coronary artery and aorta. Peripheral blood was collected for differential proteomics and microparticles analysis. Circulating interleukin (IL)-6 was analyzed. Roflumilast-treated animals displayed higher vasodilation to acetylcholine and SNP versus controls ( p < .05). Roflumilast-treated animals showed a dose-dependent ( p < .05) decrease in vessel integrity and dose-dependent increase in fibrin deposition forming a continuous layer at roflumilast-500 μg. Peripheral blood of roflumilast-500-μg-treated animals showed increased levels of total and endothelial-derived microparticles and exhibited a coordinated change in proteins kininogen-1, endothelin-1, gelsolin, apolipoprotein A-I, and apolipoprotein-J associated with vascular injury ( p < .05 vs. controls). IL-6 remained unaltered. Roflumilast-induced vascular injury can be detected by novel markers in peripheral blood. Validation of these surrogate markers in human samples seems required.