Temporal gene expression profiling indicates early up-regulation of interleukin-6 in isoproterenol-induced myocardial necrosis in rat.
Gene expression was evaluated in the myocardium of male Wistar rats after a single subcutaneous administration of 0.5 mg of isoproterenol, a beta-adrenergic agonist that causes acute tachycardia with subsequent myocardial necrosis. Histology of the heart, clinical chemistry, and hematology were evaluated at 9 time points (0.5 hours to 14 days postinjection). Myocardial gene expression was evaluated at 4 time points (1 hour to 3 days). Contraction bands and loss of cross-striation were identified on phosphotungstic acid-hematoxylin-stained sections 0.5 hours postdosing. Plasma troponin I elevation was detected at 0.5 hours, peaked at 3 hours, and returned to baseline values at 3 days postdosing. Interleukin 6 (Il6) expression spiked at 1 to 3 hours and was followed by a short-lived, time-dependent dysregulation of its downstream targets. Concurrently and consistent with the kinetics of the histologic findings, many pathways indicative of necrosis/apoptosis (p38 mitogen-activated protein kinase [MAPK] signaling, NF-kappaB signaling) and adaptation to hypertension (PPAR signaling) were overrepresented at 3 hours. The 1-day and 3-day time points indicated an adaptive response, with down-regulation of the fatty acid metabolism pathway, up-regulation of the fetal gene program, and superimposed inflammation and repair at 3 days. These results suggest early involvement of Il6 in isoproterenol-induced myocardial necrosis and emphasize the value of early time points in transcriptomic studies.
Mikaelian
Igor
I
Hoffmann-La Roche Inc., Non-Clinical Drug Safety, Nutley, New Jersey 07110, USA. igor.mikaelian@roche.com
Coluccio
Denise
D
Morgan
Kevin T
KT
Johnson
Teona
T
Ryan
Amber L
AL
Rasmussen
Erik
E
Nicklaus
Rosemary
R
Kanwal
Charu
C
Hilton
Holly
H
Frank
Karl
K
Fritzky
Luke
L
Wheeldon
Eric B
EB
D000318:Adrenergic beta-Agonists / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019210:Troponin I / Q000097:blood; D015854:Up-Regulation / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D015850:Interleukin-6; D012333:RNA, Messenger; D019210:Troponin I; D007545:Isoproterenol