Neuregulin-1β对压力超负荷心肌肥大大鼠治疗作用及机制的研究

Therapeutic effect of neuregulin-1β on pressure overload-induced myocardial hypertrophy in rats

目的:研究神经调节蛋白1β(NRG-1β)对压力超负荷所致大鼠心肌肥大的治疗作用并探讨其机制。方法:Wistar雄性大鼠采用腹主动脉缩窄的方法复制心肌肥大模型。术后8周,将模型动物随机分成模型(model)组、NRG-1β治疗组(尾静脉注射NRG-1β,10μg.kg-1.d-1)和NRG-1β+赫赛汀(Herceptin,HERCE)治疗组(尾静脉注射NRG-1β的同时给予注射HERCE 10μg.kg-1.d-1)。假手术(sham)组除不以银夹缩窄腹主动脉外,其余操作同腹主动脉缩窄组。7 d后分别采用心动超声、血流动力学评价心功能;Masson染色观察心肌组织的超微结构;放射免疫法检测心肌组织中血管紧张素II(Ang II),酶联免疫吸附法测定心肌组织中肿瘤坏死因子α(TNF-α)的变化;RT-PCR法检测心肌中bcl-2和bax mRMA表达的改变。结果:(1)心动超声显示,和模型组比较,NRG-1β组左室射血分数(LVEF)及短轴缩短率(LVFS)升高,左室收缩末内径(LVESD)及舒张末内径(LVEDD)减小(P<0.01)。(2)血流动力学检测显示,NRG-1β治疗组左室收缩末压(LVESP)和左室内压最大上升和下降速率(±dp/dtmax)均明显高于模型组(P<0.01);左室舒张末压(LVEDP)低于模型组(P<0.01)。(3)与模型组比较,NRG-1β组心肌胶原容积分数(CVF)下降,心肌中Ang II和TNF-α明显减少,bcl-2 mRNA表达显著升高,而baxmRNA表达下降(P<0.01)。(4)NRG-1β+HERCE治疗组与模型组相比各项指标无明显改变(P>0.05)。结论:NRG-1可以减少压力超负荷大鼠心肌Ang II和TNF-α的生成,从而减轻Ang II和TNF-α介导的心肌间质重构;NRG-1可通过上调bcl-2 mRNA表达、下调bax mRNA表达,抑制心肌细胞的凋亡,改善压力超负荷大鼠的心功能,进而在心肌肥大的过程中发挥作用。

AIM： To investigate the therapeutic effect and the mechanism of neuregulin-1β （NRG-1β） on the rat model of myocardial hypertrophy induced by pressure overload. METHODS： Eight weeks after coarctation of abdominal aorta, the Wistar rats were randomly divided into 4 groups： myocardial hypertrophy （model） group, sham operation （sham） group, NRG-1β treatment group （intravenous injection of NRG-I[3 at dose of 10 p,g/kg daily for 7 d） and NRG- 113 ＋ Hereeptin （HERCE） treatment group [ intravenous injection of NRG-I[3 （ 10 p^g/kg） plus HERCE （ 10 p,g/kg） daily for 7 d ]. The characteristics of heart functions were evaluated by the methods of hemodynamics and echocardiography. Masson staining was employed to observe the pathological changes of myocardial tissues. The concentration of angiotensin II （Ang II） in myocardial tissues was measured by radioimmunoassay. The level of tumor necrosis factor a （TNF-ct） in myo- cardial tissues was detected by ELISA. The mRNA expression of B-cell lymphoma/leukemia-2 （bcl-2） and bcl-2-associat- ed X protein （bax） in the myocardium was determined by RT-PCR. RESULTS： The left ventricular ejection fraction （LVEF） and left ventricular fraction shortening （LYFS） were higher, while the left ventricular end-systolic diameter （LVESD） and left ventricular end-diastolic diameter （LVEDD） were smaller in NRG-1β group than those in model group. The left ventricular end-systolic pressure （LVESP） and maximal rate of increase/decrease in left ventricular pressure （ ＋ dp/dtmas ） were higher, and left ventricular end-diastolic pressure （LVEDP） was significantly lower in NRG-1β group than those in model group. Compared with model group, treatment with NRG-1β decreased collagen volume fraction （CVF）, re-duced the Ang II and TNF-{x, increased bcl-2 mRNA expression, and decreased bax mRNA expression in myocardial tis- sues. No difference of the above parameters between model group and NRG-1 β ＋ HERCE treatment group was observed. CONCLUSION： NRG-1 reduces the expression of Ang II and TNF-ot in myocardial tissues in pressure-overload rats, thus reducing Ang II and TNF-ot mediated myocardial interstitial remodeling. Increase in the mRNA expression of bcl-2 and de- crease in the mRNA expression of bax by NRG-1 inhibit myocardial cell apoptosis, which is responsible for its role of im- proving cardiac function of myocardial hypertrophy induced by pressure overload.