Serum cardiac troponin I concentrations transiently increase in rats given rosiglitazone

Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist of the thiazolidinedione class, is a major insulin-sensitizing drug widely used to treat type-2 diabetes. Rosiglitazone causes myocardial hypertrophy in rodents and increases the risk of cardiac events in man. To better characterize its cardiac effects, male Wistar rats were orally administered 0, 10 or 80 mg/kg/day rosiglitazone. Myocardial gene expression profiling, hematology, histopathology and clinical chemistry, including measurement of serum cardiac troponin (cTn) I concentration with the ultrasensitive assay, were evaluated after 6 and 24 h and 7 and 14 days of dosing. Heart weight was increased 10% after 7 days and 16% after 14 days of dosing at 80 mg/kg/day in the absence of microscopic changes. At the transcriptomic level, the number of differentially expressed probes was small: it was most at 24 h in rats given 80 mg/kg rosiglitazone with 356 differentially regulated probes (fold change >1.3 fold, p < 0.05). Also, gene categories typically associated with myocardial damage were not over-represented. Most importantly, serum cTnI concentrations in 5/9 rats after 7 days of dosing at 80 mg/kg/day were above the upper limit of serum cTnI concentration. cTnI concentrations after 14 days of dosing were similar between rats given the vehicle and rosiglitazone at 80 mg/kg. This is the first study to detect increases of serum cTnI concentrations in rats administered rosiglitazone. In light of reported cardiac events in patients chronically dosed with PPARγ agonists, our results support serum cTnI concentrations as an early biomarker of cardiac liability.

Schlagwörter

Fachgebiet (DDC)

600 - Technik, Medizin, angewandte Wissenschaften

Projekt

Veranstaltung

Startdatum der Ausstellung

Enddatum der Ausstellung

Startdatum der Konferenz

Enddatum der Konferenz

Datum der letzten Prüfung

ISBN

ISSN

0378-4274
1879-3169

Sprache

Englisch

Während FHNW Zugehörigkeit erstellt

Nein

Zukunftsfelder FHNW

Publikationsstatus

Veröffentlicht

Begutachtung

Peer-Review der ganzen Publikation

Open Access-Status

Closed

Lizenz

Zitation

Mikaelian, I., Buness, A., Hirkaler, G., Fernandes, R., Coluccio, D., Geng, W., Visalli, T., Bachynsky, M. O., Berkofsky-Fessler, W., Kanwal, C., Hilton, H., Nicklaus, R., Hoflack, J.-C., Dunn, M., Sanders, M., Giron, M., Boyle, B. W., Singer, T., & Suter-Dick, L. (2011). Serum cardiac troponin I concentrations transiently increase in rats given rosiglitazone. Toxicology Letters, 201(2), 110–115. https://doi.org/10.1016/j.toxlet.2010.12.012

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