Effects of 3-methyladenine on isolated left atria subjected to simulated ischaemia?reperfusion

ROMINA HERMANN; DÉBORA ELISABET VELEZ; TATIANA MARIEL RUSIECKI; MARÍA DE LAS MERCEDES FERNÁNDEZ PAZOS; VICTORIA EVANGELINA MESTRE CORDERO; MARÍA GABRIELA MARINA PRENDES; JUAN CARLOS PERAZZO ROSSINI; ENRIQUE ALBERTO SAVINO; ALICIA VARELA

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2015

0305-1870

Although autophagy is a prominent feature of myocardialischaemia and reperfusion, its functional significance isunclear and controversial. In order to gain a deeper insightinto the role of autophagy in myocardial ischaemia-reperfusion,we explored the effects of the pharmacological inhibitorof autophagy 3-methyladenine (3-MA). Isolated rat atriasubjected to simulated 75-min ischaemia/75-min reperfusion(Is-Rs) in the presence or absence of 3-MA were used. TheLC3-II/LC3-I ratio, an indicator of autophagosome formation,did not increase after ischaemia either in the presenceor absence of 3-MA, but there was significant enhancementduring reperfusion, which was prevented by the presence of3-MA. The autophagy inhibitor also increased p62 protein,one of the specific substrates degraded through the autophagy-lysosomal pathway. Electron micrographs showeddouble membrane autophagosome-like structures during reperfusion,which were absent in atria subjected to Is-Rs in thepresence of 3-MA. These findings suggest that this agentinhibited the autophagic flux under the present experimentalconditions. Inhibition of autophagy during Is-Rs was accompaniedby a high incidence of tachyarrhythmias during reperfusion,and a decrease in the maximal inotropic response tob-adrenergic and to calcium stimulation at the end of Is-Rs.Deterioration of mitochondrial morphology and function,without affecting cell viability, was observed in atria subjectedto Is-Rs in the presence of 3-MA. The present resultssuggest an association between the inhibition of autophagyand functional alterations of the cells that have undergonesublethal stress, and have been able to recover in this experimentalmodel of ischaemia?reperfusion.