Protective Effect And Mechanism Of Metallothionein On Myocardial Injury Induced By Arsenic Trioxide And Obesity Additively

Objective:Arsenic trioxide is a common clinical anti-tumor drug,which is mainly used in the treatment of acute promyelocytic leukemia,breast cancer and other solid tumors.And its application in the treatment strategy of solid tumors has been widely studied.However,the cardiotoxicity caused by its application seriously hindered the strategy of treatment.At the same time,with the gradual improvement of people's substance level,the heart injury induced by obesity is very common in clinic.Unfortunately,patients with tumors also commonly suffer from heart damage induced by obesity,which greatly limits the choice of arsenic trioxide as an anti-tumor treatment.Metallothionein is an effective endogenous antioxidant,which can effectively protect cardiac myocytes from oxidative stress injury.Therefore,the purpose of this study was to prove whether metallothionein can protect cardiac myocytes and inhibit the occurrence of cardiac toxicity under the double attacks of obesity and treatment dose of arsenic trioxide.Methods:Transgenic mice with high metallothionein-specific cardiac high expression were exposed to a high-fat diet and a normal diet as control at 4 weeks old,compared with the homogeneously wild-type control mice.Glucose tolerance tests were performed four months later to detect insulin resistance in mice exposed to a high-fat diet.Subsequently,arsenic trioxide(5mg/kg/day)was injected into the tail vein,and the mice in each group were sacrificed after one month.Cardiac tissue was collected and various molecular indicators such as apoptosis,oxidative stress,inflammatory reaction and fibrosis were detected.Results:In the obese mouse model,the protective mechanism of MT could not be activated without the involvement of metal.Under the single factor attack of arsenic trioxide,MT can inhibit the oxidative stress response and protect the apoptosis ofcardiomyocytes by inhibiting the P53 signaling pathway and the three major apoptotic pathways.At the same time,it can also inhibit the activation of NF-kB signaling pathway,thereby reducing the secretion of its downstream cytokines,chemokines and adhesion molecules,and further inhibiting the recruitment of macrophages.Under the the double factors of arsenic trioxide and obesity,the oxidative stress damages of myocardial cell,including cell apoptosis,inflammation were more serious.Meanwhile,obesity increased the sensitivity of fibrosis in myocardial cell induced by arsenic trioxide,bringing forward the process of myocardial fibrosis.But in the case of a double attacks,MT also had a stronger protective effect against the damage of cardiomyocytes.Conclusion:Metallothionein has a protective effect on myocardial injury induced by arsenic trioxide and the double attacks combined with obesity.However,in the absence of metal ions,the high expression of MT alone had no protective effect on myocardial injury induced by obesity.