Regulation of autophagy factors by oxidative stress and cardiac enzymes imbalance during arsenic or/and copper induced cardiotoxicity in Gallus gallus.

Abstract Basal autophagyhas an indispensable role in the functioning and maintenance of cardiac geometry under physiological conditions. Recently, increasing evidence has demonstrated that arsenic (As)/copper (Cu) play important roles in the autophagyof the heart. The current study was to evaluate whether oxidative damage by As or/and Cu was correlated with autophagythrough the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B(AKT)/mammalian target of rapamycin (mTOR) pathway in the heart of birds. Arsenic trioxide(30 mg/kg) or/and cupric sulfate (300 mg/kg) were administered in a basal diet to male Hy-line chickens (one-day-old) for 12 weeks. The results showed that heart weight/body weight ratio decreased in the As + Cu group only at 4, 8 and 12 weeks. Moreover, we observed that As or/and Cu decreased high-density lipoprotein cholesterol (HDL-C) concentrations, increased total cholesterol (T-CHO) concentrations and cardiac enzymesactivities in the serum. On the other hand, As or/and Cu significantly reduced the activities of total antioxidant (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px)) along with decreased nonenzymic antioxidant (glutathione (GSH)) concentrations and increased malondialdehyde (MDA) concentrations in the heart. Furthermore, As or/and Cu could induce autophagyin the heart of chickens through decreased mRNA levels of TORC1, TORC2, microtubule associated light chains 3-I (LC3-I) and increased PI3K, AKT1, Beclin1, autophagyassociated gene 4B (Atg4B), microtubule associated light chains 3-II (LC3-II), autophagyassociated gene 5 ( Atg5) and Dynein. Meanwhile, ultrastructural examinations showed that As/Cu could result in the appearance of autolygosomes, autophagic vacuoles and double-membrane structures in the heart. In conclusion, As or/and Cu induced cardiac damage and autophagyvia elevating cardiac enzymesactivities, inducing oxidative stress and activating the PI3K/AKT/mTORC pathway in heart of chickens. Moreover, As and Cu had a possible synergistic relationship in the heart of chickens.