ABSTRACT
Objective To explore whether suberoylanilide hydroxamic acid (SAHA,br.Vorinostat,a kind of histone deacetylase inhibitor) can improve the diastolic function of restrictive cardiomyopathy (RCM) mice by up-regulating the expression of wild type cardiac troponin I (WT-cTnI).Methods Sixteen male cTnI R193H mice were employed and divided into SAHA group (n=6),dimethyl sulfoxide (DMSO) group (n=5) and control groups (n=5).Mice were subcutaneously injected with 50mg/kg SAHA in SAHA group,with 1ml/kg DMSO in DMSO group and with 1ml/kg normal saline in control group,respectively.The total treatment duration lasted for 56 days.Western blotting was performed to determine the levels of acetylated histone H3 (acH3) and the expression of cTnI.The transcription levels of Tnni3 were detected with RT-qPCR.The levels of acH3 in Tnni3 promoter key area were detected with chromatin immunoprecipitation (ChIP).The data of diastolic function measurements were collected using high frequency echocardiography.Results Compared to control group,the acH3 levels in nucleus and in Tnni3 promoter key area increased significantly in SAHA group (P＜0.05).The acH3 level showed no significant difference between SAHA group and DMSO group (P＞0.0S),but the specific acH3 level in Tnni3 promoter key area increased significantly in SAHA group compared to that in DMSO group (P＜0.05).The expression of cTnI protein and Tnni3 mRNA showed no significant difference among the 3 groups.Compared to the control group,Tei index and E/A ratio increased in DMSO group.Left ventricle fractional shortening (LVFS),left ventricle ejection fraction (LVEF),stroke volume (SV),cardiac output (CO),isovolumic relaxation time (IVRT),E peak deceleration time (DT),early diastolic blood flow (E velocity) and late diastolic filling flow (A velocity) showed no significant difference between DMSO group and control group.IVRT,DT and Tei index increased,and E velocity and A velocity decreased in SAHA group compared to that in control group.Furthermore,LVFS,LVEF,SV and CO were decreased in SAHA group compared to that in control group (P＜0.05).Similarly,IVRT increased (P＜0.05) and LVFS,LVEE CO,E velocity and E/A ratio decreased in SAHA group compared to that in DMSO group.Conclusions SAHA may up-regulate the acH3 level in GATA and MEF2 binding site of Tnni3 promoter of RCM mice.However,SAHA may have no effect on the expression and transcription of Tnni3 in heart.Further studies are needed to confirm whether SAHA has any toxic effect on cardiac function.