Altered gene expression in rat mesenteric tissue following in vivo exposure to a phosphodiesterase 4 inhibitor.
Vascular injury is a relatively common finding during the pre-clinical toxicity testing of drugs. The mechanisms of the injury are poorly understood and in turn, sensitive and specific biomarkers for pre-clinical and clinical monitoring do not exist. The present study was undertaken to investigate the molecular mechanisms of drug-induced vascular injury in mesenteric tissue of rats treated with the selective phosphodiesterase 4 (PDE4) inhibitor CI-1044. In a time-course study, male Sprague Dawley rats were given daily doses of 40 or 80 mg/kg for 1, 2 or 3 successive days and were euthanized the following day. Gene expression profiles in mesenteric tissue were determined using Affymetrix RG_U34A microarrays and fibrinogen and cytokine measurements were performed in blood samples. Hierarchical clustering analysis produced a clear pattern separation of the animals with inflammation, animal with inflammation and necrosis and animals without any lesion. Genes associated with inflammation, procoagulation, extracellular matrix remodeling were up-regulated. An altered expression of genes involved in vascular tone regulation, lipid and glucose metabolism was also observed. Selected genes expression changes were confirmed by TaqMan real-time RT-PCR. The inflammatory process was also detected in the bloodstream at the protein level since fibrinogen, IL6 and IL1beta concentrations were increased in treated animals. Overall, the present study reveals several molecular changes supporting the hypothesis by which PDE4 inhibitor-induced vascular lesions in rats are triggered by an inflammatory mechanism and/or a vascular tone dysregulation.
Daguès
Nicolas
N
Pfizer Global R&D, Drug Safety, Amboise, France. nicolas.dagues@pfizer.com
Pawlowski
Valérie
V
Guigon
Ghislaine
G
Ledieu
David
D
Sobry
Cécile
C
Hanton
Gilles
G
Freslon
Jean-Louis
JL
Chevalier
Stephan
S
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001381:Azepines / Q000633:toxicity*; D016000:Cluster Analysis; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D007249:Inflammation / Q000378:metabolism; D007378:Interleukins / Q000097:blood; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000473:pathology; D008643:Mesentery / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D010726:Phosphodiesterase Inhibitors / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D001381:Azepines; D007378:Interleukins; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D009536:Niacinamide; D005340:Fibrinogen; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C418118:CI 1044