The Role of Autophagy and Death Pathways in Dose-dependent Isoproterenolinduced Cardiotoxicity

Author(s): Alexandra Gyongyosi, Rita Zilinyi, Andras Czegledi, Agnes Tosaki, Arpad Tosaki, Istvan Lekli*.

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 19 , 2019

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 dosedependent 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 isoenzyme 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.

Keywords: Isoproterenol, cardiotoxicity, necrosis, apoptosis, autophagy, β-adrenergic agonist.

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Article Details

VOLUME: 25
ISSUE: 19
Year: 2019
Page: [2192 - 2198]
Pages: 7
DOI: 10.2174/1381612825666190619145025

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