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Toxicologic Pathology, Vol. 36, No. 2, 256-264 (2008) DOI: 10.1177/0192623307312696
Temporal Gene Expression Profiling Indicates Early Up-regulation of Interleukin-6 in Isoproterenol-induced Myocardial Necrosis in Rat
1 Hoffmann-La Roche Inc., Non-Clinical Drug Safety, Nutley, New Jersey, USA and Correspondence: Address correspondence to: Igor Mikaelian, Hoffmann La-Roche Inc., Non-Clinical Drug Safety, Bldg. 100/326, 340 Kingsland Street, Nutley, NJ, 07110; email: igor.mikaelian{at}roche.com.
Gene expression was evaluated in the myocardium of male Wistar rats after a single subcutaneous administration of 0.5 mg of isoproterenol, a β-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-
Key Words: Affymetrix • gene expression • isoproterenol • interleukin 6 • myocardium • rat • transcriptomic Abbreviations: A2m, alpha-2-macroglobulin • ABI, Applied Biosystems • Acta1, actin, alpha 1, skeletal muscle • AR, adrenergic receptor • AST, aspartate aminotransferase • Bcl2, B-cell leukemia lymphoma 2 • Cav, caveolin • Cebpb, CCAAT enhancer binding protein (C EBP), beta • CK, creatine kinase • Col5a2, procollagen, type V, alpha 2 • Crp, C-reactive protein • Egr1, early growth response 1 • Figf, c-fos induced growth factor • Gapdh, glyceraldehyde-3-phosphate dehydrogenase • Gucy1a3, guanylate cyclase 1, soluble, alpha 3 • Hand2, heart and neural crest derivatives expressed transcript 2 • HE, hematoxylin and eosin • Hif1a, hypoxia inducible factor 1, alpha subunit • Hp, haptoglobin • Il4, interleukin 4 • Il6, interleukin 6 • Il6st, interleukin 6 signal transducer • JAK STAT, Janus kinase-signal transduction and activation • Junb, Jun-B oncogene • KO, knock-out • Lbp, lipopolysaccharide binding protein • LDH, lactate dehydrogenase • MAPK, mitogen-activated protein kinase • Myh7, myosin, heavy polypeptide 7, cardiac muscle, beta • NF-kB, nuclear factor-kappa B • Nppa, natriuretic peptide precursor type A • PDGF, platelet derived growth factor • PPAR, peroxisome proliferator activated receptor • PTAH, phosphotungstic acid hematoxylin • Pygm, muscle glycogen phosphorylase • Rn18s, 18S RNA • RT-PCR, reverse transcriptase polymerase chain reaction • Socs3, suppressor of cytokine signaling 3 • Spp1, secreted phosphoprotein 1 • TGF, transforming growth factor • Tgfb, transforming growth factor • Timp1, tissue inhibitor of metalloproteinase 1 • Ucp2, uncoupling protein 2 (mitochondrial, proton carrier)
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B 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.