Gene profiling of the heart myocardium after a single dose administration of Isoproterenol hydrochloride

Gene expression was evaluated in the myocardium of male Wistar rats after a single sc administration of 0.5 mg of isoproterenol, a -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 hr to 14 d post-injection). Myocardial gene expression was evaluated at 4 time-points (1 hr to 3 d). Contraction bands and loss of cross striation were identified on phosphotungstic acid-hematoxylin-stained sections 0.5 hr post-dosing. Plasma troponin I elevation was detected at 0.5 hr, peaked at 3 hr, and returned to baseline values at 3 d post-dosing. Interleukin 6 (Il6) expression spiked at 1-3 hr and was followed by a short-lived time-dependant dysregulation of its downstream targets. Concurrently and consistent with the kinetics of the histologic findings, many pathways indicative of necrosis/apoptosis (p38 MAPK signaling, NF-kB signaling) and adaptation to hypertension (PPAR signaling) were over-represented at 3 hr. The 1 d and 3 d time-points indicated an adaptative response, with down-regulation of the fatty acid metabolism pathway, up-regulation of the fetal gene program, and superimposed inflammation and repair at 3 d. These results suggest early involvement of Il6 in isoproterenol-induced myocardial necrosis and emphasize the value of early time-points in transcriptomic studies

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