A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat

Eugene H. Herman, Alan Knapton, Elliot Rosen, Karol Thompson, Barry Rosenzweig, Joel Estis, Sara Agee, Quynh Anh Lu, John A. Todd, Steven E Lipshultz, Brian Hasinoff, Jun Zhang

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Cardiotoxicity was an unanticipated side effect elicited by the clinical use of imatinib (Imb). This toxicity has been examined in only a limited number of experimental studies. The present study sought, by a variety of approaches, to identify important characteristics of Imb-induced cardiac alterations. Male spontaneously hypertensive rats (SHRs) received oral doses of 10, 30, or 50 mg/kg Imb or water daily for 10 d. Cardiac lesions, detected at all doses, were characterized by cytoplasmic vacuolization and myofibrillar loss. In a second experiment, cardiac lesions were found in Sprague Dawley (SD) and SHR rats given 50 or 100 mg/kg Imb for 14 d. Mean cardiac lesion scores and serum levels of cardiac troponin I were higher in SHRs than in SD rats. Imb induced myocyte death by necrosis, autophagy, and apoptosis. Dose-related increases in cardiac expression were observed for several genes associated with endoplasmic reticulum stress response, protein folding, and vascular development and remodeling. Imb caused alterations in isolated myocytes (myofibrillar loss, highly disrupted and disorganized sarcomeric α-actinin, apoptosis, and increased lactate dehydrogenase release) at low concentrations (5 mM). The authors conclude that Imb exerts cardiotoxic effects that are manifest through a complex pattern of cellular alterations, the severity of which can be influenced by arterial blood pressure.

Original languageEnglish
Pages (from-to)1091-1106
Number of pages16
JournalToxicologic Pathology
Volume39
Issue number7
DOIs
StatePublished - Dec 1 2011

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Rats
Inbred SHR Rats
Muscle Cells
Apoptosis
Actinin
Protein folding
Endoplasmic Reticulum Stress
Troponin I
Protein Folding
Blood pressure
Autophagy
Heat-Shock Proteins
Imatinib Mesylate
Cardiotoxicity
L-Lactate Dehydrogenase
Sprague Dawley Rats
Toxicity
Arterial Pressure
Necrosis
Genes

Keywords

  • and Sprague Dawley rats
  • apoptosis
  • autophagy
  • cardiac troponin I
  • drug-induced cardiotoxicity
  • LAMP-2
  • spontaneously hypertensive rats
  • tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Toxicology
  • Cell Biology
  • Molecular Biology

Cite this

Herman, E. H., Knapton, A., Rosen, E., Thompson, K., Rosenzweig, B., Estis, J., ... Zhang, J. (2011). A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat. Toxicologic Pathology, 39(7), 1091-1106. https://doi.org/10.1177/0192623311419524

A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat. / Herman, Eugene H.; Knapton, Alan; Rosen, Elliot; Thompson, Karol; Rosenzweig, Barry; Estis, Joel; Agee, Sara; Lu, Quynh Anh; Todd, John A.; Lipshultz, Steven E; Hasinoff, Brian; Zhang, Jun.

In: Toxicologic Pathology, Vol. 39, No. 7, 01.12.2011, p. 1091-1106.

Research output: Contribution to journalArticle

Herman, EH, Knapton, A, Rosen, E, Thompson, K, Rosenzweig, B, Estis, J, Agee, S, Lu, QA, Todd, JA, Lipshultz, SE, Hasinoff, B & Zhang, J 2011, 'A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat', Toxicologic Pathology, vol. 39, no. 7, pp. 1091-1106. https://doi.org/10.1177/0192623311419524
Herman EH, Knapton A, Rosen E, Thompson K, Rosenzweig B, Estis J et al. A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat. Toxicologic Pathology. 2011 Dec 1;39(7):1091-1106. https://doi.org/10.1177/0192623311419524
Herman, Eugene H. ; Knapton, Alan ; Rosen, Elliot ; Thompson, Karol ; Rosenzweig, Barry ; Estis, Joel ; Agee, Sara ; Lu, Quynh Anh ; Todd, John A. ; Lipshultz, Steven E ; Hasinoff, Brian ; Zhang, Jun. / A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat. In: Toxicologic Pathology. 2011 ; Vol. 39, No. 7. pp. 1091-1106.
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