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

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.

ArrhythmoGenoPharmacoTherapy

“…Potential mechanisms depicted in Figure 3 show that reperfusion of the ischemic myocardium intensifies the incidence of reperfusion-induced arrhythmias, which are followed by necrosis-, apoptosis-, and autophagy-induced cell deaths (Osipov et al, 2009;Zhang et al, 2012;Chang et al, 2013;Czegledi et al, 2019;Gyongyosi et al, 2019;Yasuda et al, 2019). From a different point of view, autophagic processes may be even beneficial, depending on their intensity in reversible injured myocardial cells.…”

“…From a different point of view, autophagic processes may be even beneficial, depending on their intensity in reversible injured myocardial cells. However, necrosis-induced cell death could dominate and mask autophagic signal transduction processes and autophagyinduced cell death in myocardial tissues (Czegledi et al, 2019;Gyongyosi et al, 2019). Cellular biology and genetics have a real value and significant impact to try better to define the generation of cardiovascular diseases, including life threatening cardiac arrhythmias.…”

Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation

“…In addition, animal studies have shown that onset of ventricular fibrillation increases autophagy-associated proteins in the ventricle accompanied by myocardial damage [24][25][26], suggesting that arrhythmia itself may directly cause altered cardiac autophagy.…”

Physical Exercise and Selective Autophagy: Benefit and Risk on Cardiovascular Health

“…Isoproterenol is an extensively employed non-selective β-adrenergic agonist. It was suggested that at small dose of isoproterenol, autophagy may cope with the toxic arrhythmic effect of isoproterenol [123]. It is anticipated that non-invasive interventions such as exercise might be the countermeasure to arrhythmogenesis.…”