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 car-diac 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.
Highlights
Isoproterenol [1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol hydrochloride, ISO] is a catecholamine and bearing a nonselective β -adrenergic agonist property
Taken together these results suggest that at smaller dose of ISO autophagy may cope with the toxic effect of ISO; at higher dose apoptosis is initiated and at the highest dose substantial necrosis occurs
At low dose it can be used in heart block and cardiac arrest; at chronic or high doses, administration of ISO leads to the development of irreversible damage of the myocardium and causes infarct-like necrosis in heart muscles [1]. β-adrenergic overstimulation by ISO upset the balance between the oxygen demand and supply of the myocardium leading to pathological alterations [2]
Summary
Isoproterenol [1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol hydrochloride, ISO] is a catecholamine and bearing a nonselective β -adrenergic agonist property. At low dose it can be used in heart block and cardiac arrest; at chronic or high doses, administration of ISO leads to the development of irreversible damage of the myocardium and causes infarct-like necrosis in heart muscles [1]. The aforementioned events of ISO-induced toxicity lead to cardiac fibrosis [3, 5, 6] Previous studies on this matter showed that ISO-induced myocardial damage involves apoptosis; apoptosis seems to be an important complicating factor of myocardial injuries increasing the degree of myocyte cell death, which eventually leads to irreversible damages [7, 8].
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