title: Roflumilast-induced Local Vascular Injury Is Associated with a Coordinated Proteome and Microparticle Change in the Systemic Circulation in Pigs.
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.
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Vilahur
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Cubedo
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Padró
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Casaní
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Juan-Babot
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Crespo
authors.affiliation: Firalis SAS, Huningue, France.
authors.forename: Kaidre
authors.initials: K
authors.lastname: Bendjama
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lawton
authors.affiliation: Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain Cardiovascular Research Chair, UAB, Barcelona, Spain lbadimon@csic-iccc.org.
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
mesh_terms: D000631:Aminopyridines / Q000633:toxicity*; D000818:Animals; D001549:Benzamides / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000032:analysis / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000187:drug effects* / Q000378:metabolism; D003521:Cyclopropanes / Q000633:toxicity; D005260:Female; D015850:Interleukin-6 / Q000097:blood; D058988:Phosphodiesterase 4 Inhibitors / Q000633:toxicity; D020543:Proteome / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D013552:Swine; D057772:Vascular System Injuries / Q000097:blood* / Q000139:chemically induced*
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D015415:Biomarkers; D001798:Blood Proteins; D003521:Cyclopropanes; D015850:Interleukin-6; D058988:Phosphodiesterase 4 Inhibitors; D020543:Proteome; C424423:Roflumilast
keywords: Roflumilast; biomarkers; drug-induced vascular injury; proteomics