ABSTRACT
Arsenic trioxide (As2O3) is used to treat acute promyelocytic leukemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the human ether-a-go-go-related gene (hERG) current via disturbing its trafficking to cellular membrane. This study aimed to investigate whether the As2O3-insulted hERG channel can be rescued by resveratrol, a recognized cardioprotective agent. The whole-cell patch clamp technique was used to record the hERG current and action potential duration. Co-immunoprecipitation and Western blot assay were applied to determine the function of hERG-Hsp70/Hsp90 chaperone complexes and the expression alteration of protein-folding-related proteins, respectively. Compared with treatment of As2O3 alone, co-treatment with resveratrol successfully restored the current and surface expression of hERG and obviously shortened action potential duration in guinea pig ventricular myocytes. Further experiments demonstrate that resveratrol relieved As2O3-caused endoplasmic reticulum (ER) stress by restoring the function of hERG-Hsp70/Hsp90 chaperone complexes and downregulating the protein expression of ER chaperone proteins (calnexin and calreticulin) and activating transcription factor 6. In conclusion, resveratrol was able to rescue the trafficking deficiency and relieve the ER stress (ERS). Our findings suggest that resveratrol has a potential effect to alleviate the adverse effect of As2O3 on cardiotoxicity.
Subject(s)
Cardiotoxicity/prevention & control , Endoplasmic Reticulum Stress/drug effects , Oxides/toxicity , Stilbenes/pharmacology , Action Potentials/drug effects , Animals , Antineoplastic Agents/toxicity , Arsenic Trioxide , Arsenicals , Blotting, Western , Cardiotonic Agents/pharmacology , Cardiotoxicity/etiology , Down-Regulation/drug effects , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/deficiency , Guinea Pigs , HEK293 Cells , HSP70 Heat-Shock Proteins/metabolism , HSP90 Heat-Shock Proteins/metabolism , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Patch-Clamp Techniques , ResveratrolABSTRACT
This study was aimed to establish sensitized animal models, explore the changes of immune function in these sensitized recipients, and investigate effects of sensitization on the engraftment of hematopoietic stem cells (HSCs). Different doses of spleen cells (1x10(5), 1x10(6) and 1x10(6)x2 at intervals of 7 days) from C57BL/6 were infused into BALB/c, the immunity function of sensitized models was tested by complement-dependent cytotoxicity method, mixed lymphocyte reaction and ELISA. After irradiation with gamma-ray of 60Co in dose 8 Gy, sensitized mice were transplanted 1x10(7) C57BL/6 bone marrow cells via tail vein or intra-bone marrow, and survival rate was detected daily. The results showed that different levels of donor reactive antibody were induced in all sensitized models. Comparing with normal mice, profound proliferation of spleen cells were found in groups of injected 1x10(6) and 1x10(6), continuous injections at intervals of 7 days. Sensitized model received bone marrow cells of C57BL/6 via tail vein died on day 10 to 14 after transplantation, and sensitized model mice received bone marrow cells of 1x10(6)x2 at intervals of 7 days via intra-bone marrow also died within two weeks after transplantation. It is concluded that different sensitized mouse models are established by different doses of allogeneic spleen cells infusion, the changes of immune function in sensitized mice are correlative with sensitization. Donor HSCs are rejected in sensitized models, and the engraftment can not be improved by intra-bone marrow injection.
