The role of autophagy and death pathways in dose-dependent isoproterenol-induced cardiotoxicity

Alexandra Gyongyosi, Rita Zilinyi, Andras Czegledi, Agnes Tosaki, Arpad Tosaki, Istvan Lekli

Research output: Contribution to journalArticle

Abstract

�Background: Isoproterenol (ISO) is a non-selective β-adrenergic agonist. Our aims were to investigate the autophagy and cell death pathways including apoptosis and necrosis in ISO-induced cardiac injury in a dose-dependent manner. Methods: Male Sprague-Dawley rats were treated for 24 hours with I. vehicle (saline); II. 0.005 mg/kg ISO; III. 0.05 mg/kg ISO; IV. 0.5 mg/kg ISO; V. 5 mg/kg ISO; VI. 50 mg/kg ISO, respectively. Hearts were isolated and infarct size was measured. Serum levels of Troponin T (TrT), lactate dehydrogenase (LDH), creatine kinase iso-enzyme MB (CK-MB) were measured. TUNEL assay was carried out to monitor apoptotic cell death and Western blot was performed to evaluate the level of autophagic and apoptotic markers. Results: Survival rate of animals was dose-dependently decreased by ISO. Serum markers and infarct size revealed the development of cardiac toxicity. Level of Caspase-3, and results of TUNEL assay, demonstrated that the level of apoptosis was dose-dependently increased. They reached the highest level in ISO 5 and it decreased slightly in ISO 50 group. Focusing on autophagic proteins, we found that level of Beclin-1 was increased in a dose-dependent manner, but significantly increased in ISO 50 treated group. Level of LC3B-II and p62 showed the same manner, but the elevated level of p62 indicated that autophagy was impaired in both ISO 5 and ISO 50 groups. Conclusion: Taken together these results suggest that at smaller dose of ISO autophagy may cope with the toxic effect of ISO; however, at higher dose apoptosis is initiated and at the highest dose substantial necrosis occurs.

Original languageEnglish
Pages (from-to)2192-2198
Number of pages7
JournalCurrent pharmaceutical design
Volume25
Issue number19
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • Apoptosis
  • Autophagy
  • Cardiotoxicity
  • Isoproterenol
  • Necrosis
  • β-adrenergic agonist

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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