The Study On Dityrosine-induced Myocardial Injury And Energy Metabolism Disorder In Mice

Tyrosine is easily oxidized during food processing and storage to produce tyrosine oxidation products?OTPs?.Previous studies have found that ingestion of OTPs caused oxidative stress in body tissues and organs?eg,liver,kidneys,myocardium,pancreas,brain,and intestines?,leading to tissue damage.Dityr is the main component of OTPs and the structure of Dityr is stable and similar to thyroid hormones.In this study,60 healthy female Kunming mice were randomly divided into 3 groups:the control group?Con?,oxidized tyrosine products group?OTPs?and dityrosine group?Dityr?,mice in the OTPs and Dityr group were gavaged at a dose of 960?g/kg bw OTPs and 320?g/kg bw Dityr,and mice in Con group was gavaged with the same amount of 0.9%saline every day for 10 weeks.Physiological and biochemical indicators were detected to investigate the effect of Dityr on myocardial function impairment and energy metabolism in mice.First of all,according to the results of metabonomics of mice gavaged for 6 weeks,OTPs and Dityr induced the changes of small molecule metabolites about oxidative stress and energy metabolism.The increase of trimethylamine in plasma and urine indicated that OTPs and Dityr may cause damage to myocardium.OTPs and Dityr also caused changes in intestinal microbiota function,decreased cholinergic bioavailability,caused changes in amino acid metabolism.Then according to the results of the 10 weeks gavage experiment,OTPs and Dityr significantly enhanced the levels of free radicals?ROS?,protein oxidation products?Dityr,AOPPs and 3-NT?and lipid oxidation products?MDA??P<0.05?,and significantly improved the deposition of Dityr by 5.6-fold and 5.1-fold in myocardium?P<0.01?.OTPs and Dityr significantly caused the decrease of redox status-related indicators?T-AOC,GSH/GSSG?in mice plasma and myocardium?P<0.01?.OTPs and Dityr significantly enhanced the levels of inflammatory factors?CRP,TNF-?and Hcy?in plasma?P<0.05?and significantly upregulated the mRNA level of genes about myocardial inflammation?NF-?B,TNF-?,IL-6and IL-1???P<0.05?.OTPs and Dityr significantly increased indicators of myocardial injury?CK,CK-MB and cTnI?in plasma?P<0.01?.The results of HE staining and Masson staining showed that OTPs and Dityr caused the infiltration of myocardial inflammatory cells,increasing the area of myocardial collagen by 2.8-fold and 3.2-fold respectively in myocardium,and had a tendency to induce myocardial fibrosis.The current study investigated indicators about energy metabolism.OTPs and Dityr inhibited myocardial energy metabolism.OTPs and Dityr significantly decreased the contents of ATP by 44%and 33%respectively in myocardium?P<0.01?.OTPs and Dityr significantly enhanced the contents of free fatty acid?FFA?in plasma and myocardium,and significantly decreased the activities of ATPase(Na⁺-K⁺-ATPase,Ca²⁺-ATPase,and LDH)in myocardium?P<0.05?.OTPs and Dityr significantly downregulated the mRNA level of genes about myocardial energy metabolism?AMPK,PPAR?and PGC-1???P<0.05?.OTPs and Dityr significantly downregulated the mRNA level of genes about myocardial fatty acid oxidation?FACS,CPT-I,and MCAD??P<0.05?.OTPs and Dityr significantly upregulated the m RNA level of genes about glucose metabolism?PDK4,GLUT1,and GLUT4??P<0.05?but significantly downregulated the mRNA level of genes about glycolysis and tricarboxylic acid cycle?P<0.05?.At last,this study used dual luciferase reporter gene system to explore the factors affecting myocardial energy metabolism.Results showed that OTPs and Dityr elevated the levels of T3 and T4 in plasma?P<0.05?,and downregulated the mRNA level of genes about myocardial thyroid hormones?TR?1,TR?1,RXR?,Src-1?.Dityr and T3 have a competitive relationship for the binding to thyroid hormone receptors,inhibiting thyroid hormones playing a role on myocardium of mice.In conclusion,OTPs and Dityr induced myocardial oxidative stress,resulted in the accumulation of myocardial protein oxidation products and lipid oxidation products,caused myocardial injury and inflammation.OTPs and Dityr interfered with thyroid hormones in mice,resulting in myocardial energy metabolism disorders in mice myocardium,and reduced myocardial ATP synthesis,which increased the risk of cardiovascular diseases in mice.The injury caused by Dityr was consistent with the performance of OTPs.Dityrosine played an important role in the process of myocardial injury in mice.