PPAR-α激活对ET-1诱导的心肌肥大和转录因子NFATc4的影响  

Effects of PPAR-α activation on ET-1-induced cardiomyocyte hypertrophy and regulation of NFATc4

作　　者：李瑞芳[1] 段冷昕[1] 乐康[2] 王平[2] 高洁[2] 杨国庆[2] 刘培庆[2] 

机构地区：[1]河南科技大学医学院药理教研室,河南洛阳471003 [2]中山大学药学院药理毒理实验室,广东广州510080

出　　处：《中国病理生理杂志》2009年第6期1046-1050,共5页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.30772576);广东省自然科学基金重点资助项目(No.7117380)

摘　　要：目的:研究过氧化物酶体增殖物激活受体-α(PPAR-α)激活对内皮素-1(ET-1)诱导的心肌肥大和活化T细胞核因子c4(NFATc4)的影响,探讨在心肌肥大发病过程中PPAR-α和NFATc4的相互作用。方法:培养新生SD大鼠心肌细胞,采用[3H]亮氨酸法和RT-PCR法观察PPAR-α激动剂非诺贝特对ET-1诱导的心肌细胞肥大的影响;应用免疫荧光和免疫共沉淀技术分别检测非诺贝特对ET-1诱导的NFATc4核转位以及PPAR-α和NFATc4相互作用的影响;用Western blotting法检测NFATc4的胞浆和胞核表达。结果:(1)PPAR-α激动剂非诺贝特显著抑制ET-1诱导的肥厚反应。(2)非诺贝特阻止ET-1诱导NFATc4由胞浆到胞核的转位。(3)在心肌细胞中,PPAR-α和NFATc4之间存在相互作用,非诺贝特加强了这种相互作用。结论:PPAR-α激活后可以通过调控转录因子NFATc4来抑制ET-1诱导的心肌肥大反应。AIM ： To investigate the effects of peroxisome proliferator - activated receptor - α （ PPAR - or） activation on ET - 1 - induced cardiomyocyte hypertrophy and the interaction of PPAR - α with nuclear factor of activated T cell （NFAT）c4 in cardiac myocytes. METHODS： Cultured cardiac myocytes of neonatal SD rats were used to establish the experiment models. [ 3H ] leucine incorporation assay was performed to examine protein ＇ synthesis while reverse tran- scription- pelymerase chain reaction （RT - PCR） was applied to analyze the mRNA level of atrial natriuretic factor （ANF）. Immunofluorescence and confocal microscopic assay were used to evaluate the effects of PPAR - α activator fenofibrate on the nuclear translocation of NFATc4. Immunoprecipitation was performed to examine the association of PPAR - α with NFATc4 in cardiomyocytes. Western blotting analysis was performed to investigate the cytoplasmic and nuclear protein levels of NFATc4. RESULTS ： （ 1 ） ET - 1 significantly increased incorporation of [ 3 H ] leucine （ 1.73± 0. 08 fold vs control, P 〈0. 01 ） and the level of ANF mRNA （ 1.74±0.25 fold vs control, P 〈0. 01 ）. However, PPAR - α activator fenofibrate （10 μmol/L） significantly inhibited the ET- 1 -induced protein incorporation in cardiomyocytes （ -31% at 5 μmol/L, -49% at 10 μmol/L） and the expression of ANF mRNA in these cells （ 1.10 ±0. 17 fold of control）. （2） ET - 1 stimulation markedly changed the translocation of NFATc4 from the cytoplasm to the nucleus while fenofibrate prevented this effect of ET - 1. （3） The interactions between PPAR - α and NFATc4 were constitutively detectable while fenofibrate further increased the interaction between NFATc4 and PPAR - α. CONCLUSION： Activation of PPAR - α prevents ET - 1 - induced cardiac myocyte hypertrophy through negative regulation of NFATc4, possibly via blocking the nuclear translocation of NFATc4 and increasing the interaction of PPAR - α and NFATc4.

关 键 词：内皮缩血管肽1 心肌肥大 过氧化物酶体增殖物激活受体Α 活化T细胞的核因子 

分 类 号：R541[医药卫生—心血管疾病]