本文選題：限制型心肌病 + HDAC抑制劑　； 參考：《解放軍醫(yī)學雜志》2017年12期

【摘要】：目的探討組蛋白去乙�；敢种苿┬炼１桨樊惲u肟酸(SAHA,商品名伏立諾他)是否能通過提高限制型心肌病小鼠野生型心肌肌鈣蛋白I(WT-cTnI)的表達以改善其舒張功能。方法選取雄性3月齡cTnI R193H限制型心肌病模型小鼠16只并隨機分為SAHA組(n=6)、二甲基亞砜(DMSO)組(n=5)和對照組(n=5),分別給予SAHA 50mg/kg、DMSO 1ml/kg、生理鹽水1ml/kg皮下注射,持續(xù)56d。采用Western blotting檢測小鼠心肌細胞核組蛋白H3的乙�；�(acH3)及cTnI蛋白表達水平,采用染色質(zhì)免疫共沉淀法(Ch IP)比較cTnI編碼基因Tnni3啟動子GATA和MEF2關鍵區(qū)域acH3水平,采用熒光定量PCR檢測Tnni3的mRNA表達水平,應用小動物高頻超聲儀評估小鼠心功能。結(jié)果與對照組比較,SAHA組心肌細胞核acH3水平和Tnni3啟動子關鍵區(qū)域acH3水平均明顯升高(P0.05);與DMSD組比較,SAHA組心肌細胞核acH3水平無明顯改變(P0.05),Tnni3啟動子關鍵區(qū)域的acH3水平明顯升高(P0.05)。3組cTnI蛋白和Tnni3mRNA表達水平差異無統(tǒng)計學意義(P0.05)。與對照組比較,DMSO組心臟收縮指標左室縮短分數(shù)(LVFS)、左室射血分數(shù)(LVEF)、每搏輸出量(SV)、心輸出量(CO)及舒張指標等容舒張時間(IVRT)、E峰減速時間(DT)、舒張早期充盈血流(E峰)、舒張晚期充盈血流(A峰)無明顯改變(P0.05),Tei指數(shù)及E/A比值明顯升高(P0.05);SAHA組IVRT、DT明顯延長(P0.05),Tei指數(shù)明顯增高(P0.05),E峰、A峰明顯降低(P0.05),E/A比值明顯改變,LVFS、LVEF、SV、CO明顯降低(P0.05)。與DMSO組比較,SAHA組IVRT明顯升高(P0.05),E峰、E/A比值明顯下降(P0.05),LVFS、LVEF、CO明顯降低(P0.05)。結(jié)論 50mg/kg SAHA干預可上調(diào)限制型心肌病小鼠心肌細胞Tnni3啟動子GATAMEF2區(qū)域acH3水平,但對cTnI蛋白和Tnni3 mRNA表達以及心臟舒張功能可能沒有改善作用,甚至會損害其舒張功能和收縮功能。
[Abstract]:Objective to investigate whether histone deacetylase inhibitor octathioxime hydroxamic acid (commercial name volenotta) can improve diastolic function by increasing the expression of wild type cardiac troponin (WT-cTnI) in mice with restricted cardiomyopathy. Methods Sixteen male 3-month-old cTnI R193H model mice were randomly divided into SAHA group (n = 6), dimethyl sulfoxide group (n = 5) and control group (n = 5). They were given SAHA 50 mg / kg DMSO 1 ml / kg and saline 1ml/kg subcutaneously for 56 days. Western blotting was used to detect the acetylation level of histone H3 and the expression of cTnI protein in murine myocardium. The levels of GATA and acH3 in the key regions of Tnni3 promoter and MEF2 were compared by chromatin immunoprecipitation method. The mRNA expression of Tnni3 was detected by fluorescence quantitative PCR, and the cardiac function of mice was evaluated by high frequency ultrasound in small animals. Results compared with the control group, the nuclear acH3 level and the acH3 level of the key region of the Tnni3 promoter in the SAHA group were significantly higher than those in the control group, while the level of acH3 in the myocardial nucleus of the SAHA group did not change significantly compared with the control group, and the acH3 level in the key region of the Tnni3 promoter was significantly higher in the SAHA group than in the DMSD group. There was no significant difference in the expression of cTnI protein and Tnni3mRNA between the two groups. Compared with the control group, the left ventricular contraction index (LVFSV), left ventricular ejection fraction (LVEFN), left ventricular ejection fraction (LVEFV), ventricular output volume (SVV), cardiac output volume (CO) and diastolic index (isovolumic diastolic time) and diastolic index (isovolumic relaxation time) were measured in DMSO group. There was no significant change in P 0.05 Tei index and E / A ratio in late filling group. In P0.05ASAHA group, the IVRTDT was significantly prolonged, P0.05 Tei index was significantly increased and P0.05 / E peak was significantly decreased, and the ratio of LVFSV, LVEFSVV, CO was significantly decreased, and P0.05 was significantly decreased in the group of P0. 05% of SAHA, P 0. 05%, P 0. 05%, P 0. 05, P 0. 05, P 0. 05, P 0. 05, P 0. 05, P 0. 05, P 0. 05, P 0. 05, P 0. 05. Compared with DMSO group, IVRT in SAHA group was significantly higher than that in DMSO group. Conclusion 50mg/kg SAHA intervention can up-regulate the level of acH3 in the GATAMEF2 region of Tnni3 promoter of cardiac myocytes in mice with restricted cardiomyopathy, but it may not improve the expression of cTnI protein and Tnni3 mRNA and the diastolic function of the heart, and even damage its diastolic and systolic function.
【作者單位】： 重慶醫(yī)科大學附屬兒童醫(yī)院心臟內(nèi)科 兒童發(fā)育疾病研究教育部重點實驗室 兒童發(fā)育重大疾病國家國際科技合作基地 兒科學重慶市重點實驗室;佛羅里達州大西洋大學醫(yī)學院生物醫(yī)學科學系;
【基金】：國家自然科學基金面上項目(31271218)~~
【分類號】：R542.2

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