伏立诺他对限制型心肌病小鼠心脏舒张功能障碍的影响

发布时间：2018-06-01 13:47

  本文选题：限制型心肌病 + HDAC抑制剂　； 参考：《解放军医学杂志》2017年12期

【摘要】：目的探讨组蛋白去乙酰化酶抑制剂辛二酰苯胺异羟肟酸(SAHA,商品名伏立诺他)是否能通过提高限制型心肌病小鼠野生型心肌肌钙蛋白I(WT-cTnI)的表达以改善其舒张功能。方法选取雄性3月龄cTnI R193H限制型心肌病模型小鼠16只并随机分为SAHA组(n=6)、二甲基亚砜(DMSO)组(n=5)和对照组(n=5),分别给予SAHA 50mg/kg、DMSO 1ml/kg、生理盐水1ml/kg皮下注射,持续56d。采用Western blotting检测小鼠心肌细胞核组蛋白H3的乙酰化水平(acH3)及cTnI蛋白表达水平,采用染色质免疫共沉淀法(Ch IP)比较cTnI编码基因Tnni3启动子GATA和MEF2关键区域acH3水平,采用荧光定量PCR检测Tnni3的mRNA表达水平,应用小动物高频超声仪评估小鼠心功能。结果与对照组比较,SAHA组心肌细胞核acH3水平和Tnni3启动子关键区域acH3水平均明显升高(P0.05);与DMSD组比较,SAHA组心肌细胞核acH3水平无明显改变(P0.05),Tnni3启动子关键区域的acH3水平明显升高(P0.05)。3组cTnI蛋白和Tnni3mRNA表达水平差异无统计学意义(P0.05)。与对照组比较,DMSO组心脏收缩指标左室缩短分数(LVFS)、左室射血分数(LVEF)、每搏输出量(SV)、心输出量(CO)及舒张指标等容舒张时间(IVRT)、E峰减速时间(DT)、舒张早期充盈血流(E峰)、舒张晚期充盈血流(A峰)无明显改变(P0.05),Tei指数及E/A比值明显升高(P0.05);SAHA组IVRT、DT明显延长(P0.05),Tei指数明显增高(P0.05),E峰、A峰明显降低(P0.05),E/A比值明显改变,LVFS、LVEF、SV、CO明显降低(P0.05)。与DMSO组比较,SAHA组IVRT明显升高(P0.05),E峰、E/A比值明显下降(P0.05),LVFS、LVEF、CO明显降低(P0.05)。结论 50mg/kg SAHA干预可上调限制型心肌病小鼠心肌细胞Tnni3启动子GATAMEF2区域acH3水平,但对cTnI蛋白和Tnni3 mRNA表达以及心脏舒张功能可能没有改善作用,甚至会损害其舒张功能和收缩功能。
[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.
【作者单位】： 重庆医科大学附属儿童医院心脏内科 儿童发育疾病研究教育部重点实验室 儿童发育重大疾病国家国际科技合作基地 儿科学重庆市重点实验室;佛罗里达州大西洋大学医学院生物医学科学系;
【基金】：国家自然科学基金面上项目(31271218)~~
【分类号】：R542.2

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