非诺贝特治疗大鼠左心室肥厚  

Non Blood Pressure Lowering Preventive Effects of Fenofibrate on Cardiac Hypertrophy in Rats

作　　者：李瑞芳[1] 高洁[2] 乐康[2] 杨国庆[2] 陈少锐[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：《中华高血压杂志》2008年第5期445-449,共5页Chinese Journal of Hypertension

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项目(No:7117380)

摘　　要：目的研究非诺贝特逆转腹主动脉缩窄(AAC)大鼠左心室肥厚的作用,并初步探讨其对 Akt/GSK3β信号通路的影响。方法采用 AAC 法建立心肌肥厚模型。术前1周和术后4周灌胃给予非诺贝特[80 mg/(kg·d)],观察了其对血流动力学参数、超声参数、左室质量(LVM)/体质量(BM)、心肌超微结构的影响。同时检测了心肌组织中 Akt 和 GSK3β蛋白磷酸化的表达变化。结果 1)与假手术组相比,大鼠腹主动脉缩窄4周后,主动脉收缩压(AoSP)、主动脉舒张压(AoDP)、左室内压(LVESP、LVEDP)明显升高(P<0.05);室内压最大上升速率(+dp/dt_(max))和室内压最大下降速率(-dp/dt_(min))明显减少(P<0.05),而非诺贝特治疗后,+dp/dt_(max)、-dp/dt_(min)明显上升(P<0.05);AoSP、AoDP、LVESP 无明显变化(P>0.05)而 LVEDP 稍降(P<0.05)。2)手术后4周 AAC 大鼠呈现出明显的向心性肥厚,室间隔(IVSd 和 IVSs)及左室后壁厚度(PWTd 和 PWTs)(P<0.05)、LVM/BM[LVM:(2.94±0.16)mg 比BM:(2.05±0.11)g,P<0.05]和心肌细胞横切面积均明显增加。经非诺贝特治疗后,左室肥厚明显逆转(P<0.05)。3)非诺贝特防止了 AAC 大鼠左心室中 Akt/GSK3β磷酸化水平的增加(P<0.01)。结论非诺贝特对升高血压无明显影响情况下,能防止 AAC 大鼠左心室肥厚,改善左室功能,抑制 Akt/GSK3β信号通路的激活。Objective To investigate the effects of fenofibrate on cardiac hypertrophy induced by abdominal aortic coarctation （AAC） and phosphorylation of glycogen synthase kinaseβ （GSK3β） in myocardium. Methods Male SD rats were randomly grouped as follows： sham-operated rats; sham-operated rats with fenofibrate treatment [80 mg/kg per day by gavage） ; AAC rats; AAC rats with fenofibrate treatment （80 mg/kg per day, by gavage） for 4 weeks. Blood pressure and hemodynamics parameters were measured by catheterigation. The eehocardiographic parameters were measured by ATL5000 ultrasound system. Left ventricular mass（LVM） to calculated body mass（BM） ratio was determined. Phosphorylation of protein kinase B （Akt） and GSK3β in myocardium were assessed by Western-blot analysis. Results Fenofibrate slightly and non-significantly decreased SBP and DBP in AAC rats. Compared with sham-operated group, left ventricular end-systolic pressure （ LVESP）, left ventricular end-diastolic pressure （LVEDP）, aortic systolic pressure （AoSP） were significantly increased with concurrently decreased in LV ＋ dP/dtmax and -dP/dtmim） in AAC rats. Fenofibrate partially reversed these systolic and diastolic dysfunction. ACC rats had significant increases in interventricular septum thickness （IVSTs and IVSTd） and posterior wall thickness （PWTs and PWTd） and decrease in left ventricular end-systolic diameter （LVESD）. Fenofibrate partly reversed these parameters of left ventricular concentric hypertrophy along with increases in phosphorylation of Akt and GSK3β in myocardium. Conclusion Fenofibrate inhibited left ventricle（LV） remodeling and hypertrophy independently in the presence of slightly; but non-significantly deareases in blood pressure in ACC rats, which was associated with significantly decreases in PI3K/Akt/GSK3β phosphorylation in myocardium. After treatment with fenofibrate, these parameters were markedly reversed, and partly reversed the increase of phosphorylation of Akt and GSK3�

关 键 词：压力超负荷 心肌肥大 过氧化物酶体增殖物活化型受体α 糖原合成酶激酶3Β 

分 类 号：R541[医药卫生—心血管疾病]