G-CSF对压力超负荷引起的心室重构和心力衰竭的影响

The effects of G-CSF on pressure overload induced ventricular remodeling and heart failure in mice

目的探讨粒细胞集落刺激因子(granulocyte colony stimulating factor,G-CSF)对压力超负荷引起的心室重构和心力衰竭发生发展的影响及其机制。方法实验动物分成7组:PBS组小鼠(PBS组)、替米沙坦组小鼠(ST组)、G-CSF(A)组小鼠(GA组)、G-CSF(B)组小鼠(GB组)、G-CSF +替米沙坦组小鼠(GT组)、替米沙坦+G-CSF组小鼠(TG组)和假手术组小鼠(sham组)。小鼠经缩窄升主动脉后,在不同时间皮下注射G-CSF或(和)替米沙坦,每周做心脏超声检测心脏功能和形态变化,分别于第1周、2周和4周末测量有侧颈动脉压后取材,用HE染色、Masson三色染色观察心脏形态变化,用Western blotting检测血管内皮生长因子(vascular endothelial growth factor,VEGF)和RT-PCR检测缺氧诱导因子1(hypoxia-inducible factorl,HIF-1)、p53mRNA的表达情况。结果(1)在0～14 d,缩窄升主动脉的小鼠心室擘厚度值逐渐升高达高峰,14～28 d PBS组厚度逐渐降低,同时伴有左室射血分数的下降,而给予G-CSF皮下注射的小鼠未见有降低,也未见有射血分数的下降;(2)同PBS组比较,VEGF蛋白、HIF-1mRNA表达存给予G-CSF皮下注射的小鼠显著升高,而p53mRNA表达、心脏纤维化程度和死亡率在给予G-CSF组显著降低。结论G-CSF通过调控血管新生,改善了压力超负荷引起的心室重构和心力衰竭,其中调控HIF-1的表达可能起着重要的作用。

Objective To explore the effects of granulocyte colony stimulating factor （G-CSF） on pressure overload induced ventricular remodeling and heart failure in mice and its mechanism. Methods Eighty six male mice were divided into seven groups： PBS group （PBS, n = 14 ） , telmisartan group （ST, n = 12）, G-CSF（A） group （GA, n=12）, G-CSF（B） group （GB, n = 12）, G-CSF combined with telmisarran group （GT, n = 12） , telmisartan combined with G-CSF group （TG, n = 12） and sham-operated group （Sham, n = 12）. The transverse ascending aorta constriction （TAC） in six groups were performed in order to make heart failure model. Mice in each group were injected with G-CSF or/and telmisartan subcutaneously at different time respectively. Cardiac function was assessed by echocardiography every week after TAC. Animals were sacrificed in batches at 1,2 and 4 weeks postoperatively after blood pressure of right carotid artery was measured. Morphological change in left ventricle were detected by HE staining, Masson staining. The expression of vascular endothelial growth factor （VEGF） in myocardium was detected by Western blotting. The mRNA expression of p53 and hypoxia-inducible factor 1 （ HIF-1 ） in myocardium were detected by semiquantitative RT-PCR. Results （ 1 ） The end-systolic thickness of left ventricular wall （ LVWTs ） in PBS group increased gradually and reached peak at 14 days, then decreased gradually with left ventricular ejection fraction （LVEF） from 14 to 28 days. LVWTs increased gradually in mice injected with G-CSF during 14 days, but there was no significant change with LVEF from 14 to 28 days （P 〈 0.05 ）. （2） Compared with PBS group, the expression of VEGF protein and HIF-lmRNA were significantly higher in mice injected with G- CSF or/and telmisartan（P 〈 0.05 ）. The expression of p53 mRNA, myocardial fibrosis and mortality were significantly lower in mice injected with G-CSF or/ and telmisartan （P 〈 0.05 ）. Conclusion G-CSF can delay the progression of pressure overload induced ventricular remodeling and heart failure in mice. The regulation of HIF-1 maybe an important underlying mechanism.