Histone Deacetylase Inhibitors TSA Attenuates Cardiotoxicity Of Adriamycin By Upregulating Proteins Expression GATA₄/Bcl₂

Objecticve:Adriamycin?ADR?is a commonly used anticancer drug in clinic.ADR belongs to cell cycle non-specific antitumor drugs andit is widely used in the treatment of leukemia and all kinds of solid tumors.But the ADR's dose-dependent cardiotoxicity limits it's clinical application in tumor treatment.Histone deacetylase inhibitors?HDACi?is another kind of antitumor drug,in addition to it's antitumor effect,it also has cardioprotection effect.In this study,ADR was used to induce myocardial injury model in rats.The histone deacetylase inhibitor,TSA?Trichostatin A?,was given during modeling.The effects of TSA on myocardial damage caused by ADR were observed by functional,morphological and molecular biology methods.And the role of proteins GATA₄/Bcl₂ in this process was further explored.Methods:Male SD rats were randomly divided into four groups?n=15?,measuring weight once every five days.?1?Saline solution control group:the start and end 3 consecutive days of the experiment,intraperitoneal inject saline solution every day;Starting from the fourth day once every other day,in all 7 times injection.The experimental treatment is totally 20 days.?2?ADR group:the start and end 3 consecutive days of the experiment,intraperitoneal inject saline solution every day;Starting from the fourth day inject ADR(3mg kg^-1)once every other day,in all 7 times injection.?3?TSA group:the start and end 3 consecutive days of the experiment,intraperitoneal inject TSA(0.5mg kg^-1)every day;Starting from the fourth day once every other day,in all 7times injection.?4?TSA+ADR group:the start and end 3 consecutive days of the experiment,intraperitoneal inject TSA(0.5mg kg^-1)every day;Starting from the fourth day inject TSA(0.5mg kg^-1),30 minutes later,then intraperitoneal inject ADR(3mg kg^-1)once every other day,in all 7 times injection.At 24 hours after the end of the total administration,the rats were anesthetized,then the cardiovascular parameters were measured in vivo,including systolic arterial pressure?SAP??diastolic arterial pressure?DAP??mean arterial pressure?MAP??left ventricular systolic pressure?LVSP??the maximal rate of rise of left ventricular pressure?+LVPdP/dt??the maximal rate of of descent left ventricular pressure?-LVPd P/dt?and left ventricular end diastolic pressure?LVEDP?.Left ventricular tissue was collected and stained with HE and TUNEL to observe the changes of myocardial cytology.Western blotting was used to detect the expression of GATA₄ and Bcl₂ protein.Rsults:1 The effect on body weight of rats during the modelingDuring the experiment,there is no significant difference between the groups in body weight of rats?P>0.05?.2 The influence of TSA on the cardiovascular functional parameters changes induced by ADR under anesthesia.Compared with the control group,the SAP?DAP?MAP?LVSP?+LVPdP/dt and-LVPdP/dt of the ADR group was all decreased?P<0.05?.Using TSA could eliminate the impact of ADR on SAP,DAP,and MAP?P<0.05??partly inhibit the reduction of LVSP?+LVPdP/dt?-LVPdP/dt caused by ADR?P<0.05?,but there is no influence on the rise of LVEDP?P>0.05?.There is no significant difference between the control group and TSA group in the cardiovascular function parameters?P>0.05?.3 The influence of TSA on the myocardial morphologic damage induced by ADRCompared with the control group,the myocardial tissue section of ADR group stained with HE showed that the myocardium was disordered,and some of the myocardial cells were broken and lost,vacuolar degeneration and atrophic cardiomyocytes were increased.Treatment of TSA can improve myocardial morphology changes and muscle cells arrangement caused by ADR,as well as reduce the atrophied myocardial cells.4 The influence of TSA on the myocardial apotosis induced by ADRCompared with control group,the apoptosis of cardiomyocytes in ADR group was significantly increased?P<0.05?.TSA treatment can partially inhibit ADR-induced cardiomyocyte apoptosis?P<0.05?.The number of apoptotic cells in cardiomyocytes of TSA group was not significantly different from that of control group?P>0.05?.5 The influence of TSA on the GATA₄ and Bcl₂ protein expression changes in myocardial cells induced by ADR.Compared with the control group,the GATA₄ and Bcl₂ protein expressions are obviously decreased in the ADR group?P<0.05?.Treatment of TSA can partly inhibit the effect caused by ADR?P>0.05?.There are no significant differences between the control group and TSA group in the the GATA4 and Bcl2 protein expression of myocardial cells?P>0.05?.Conclusions:1 TSA can effectively inhibit the functional myocardial damage caused by ADR.2 TSA can inhibit myocardial morphologic damage caused by ADR,and induce myocardial apoptosis.3 The TSA's resistance to the cardiotoxicity caused by ADR is associated with it's upregulating GATA₄/Bcl₂.