摘要
目的：利用粒细胞集落刺激因子(granulocyte colony-stimulating factor,G-CSF)动员骨髓干细胞治疗心肌梗死后心室重塑，已在一些动物研究和临床试验中证实具有很好的改善作用，但其疗效和涉及的机制仍然存在诸多分歧和争议。G-CSF动员的CRCR4~+骨髓干细胞释放到外周血后，在局部缺血组织中高表达的基质细胞衍生因子(stromal cell-derived factor，SDF)-1的趋化作用下募集到靶组织并形成CXCR4／SDF-1复合体，进而发挥作用，我们称之为G-CSF的“CXCR4效应”；此外G-CSF所发挥的效应都可归结为“非CXCR4效应”，如直接与局部心肌G-CSF受体作用后活化Jak2-Stat3信号通路抗细胞凋亡。本研究旨在观察G-CSF对缺血／再灌注心肌梗死后心室重塑和心脏功能的作用，并引入CXCR4受体拮抗剂AMD3100，系统评价G-CSF介导的“CXCR4效应”和“非CXCR4效应”对心肌梗死修复近期和远期的影响。
研究内容与方法：129只雄性Wistar大鼠，成功建立心肌缺血／再灌注(ischemiareperfusion，I/R)模型后，随机分为即刻给药组(再灌注1h即刻给药，Immediately，以下简称为I)或延迟给药组(再灌注后24小时给药，Delay，以下简称为D)；依据给药方案不同，分为单独G-CSF治疗组(I-G组和D-G组)或G-CSF与AMD3100(CXCR-4拮抗剂)联合治疗组(I-GA组和D-GA组)。术后7天和3个月时分别将大鼠处死，取心脏行病理学分析和蛋白水平测定。3月观察组大鼠在处死前采用Millar2F SPR320压力导管经右侧颈动脉穿刺进入左心室测量左室功能。采用苦味酸天狼猩红-偏振光法对心肌梗死区胶原纤维沉积量和成熟度进行病理学分析；采用FITC标记的α-SMA行免疫荧光染色对梗死区和非梗死区新生小动脉密度进行分析；采用麦胚凝集素染色分析室间隔存活心肌细胞横截面积；利用明胶酶谱法检测梗死区基质金属蛋白酶(matrix metalloproteinase，MMP)-2、9的蛋白活性；利用western blot检测梗死区MMP-2、9、组织型基质金属蛋白酶抑制剂(tissue inhibitor of matrix metalloproteinase，TIMP)-1、2以及转化生长因子(transforming growth factor，TGF)-β_1、SDF-1和血管内皮生长因子(vascular endothelial growth factor，VEGF)的蛋白相对含量。
结果：I／R术后7天，G-CSF与AMD3100联合治疗组大鼠外周血单核细胞数量明显增加(P＜0．05)；即刻G-CSF治疗组梗死范围与延迟G-CSF治疗组比较在数值上有所减少(P=0．05)：各I／R手术组梗死区小动脉密度较假手术组明显增加(P＜0．05)。
I／R术后3个月，①与对照组比较，即刻G-CSF治疗显示左室重塑加重，如左室游离壁厚度(P=0．056)和室间隔厚度(P=0．031)减小，膨展指数增加(P=0．056)，梗死范围增加(P=0．301，vs 3m-saline组；P＜0．05，vs 7d-I-G组)，室间隔心肌细胞横截面积增大(P＜0．05)；且左室功能明显恶化，左室舒张末压(left ventricular diastolic pressure，LVDP)明显增高(P＜0．05)，左室内压力最大上升和下降速度(±dP／dt_(max))减低(P=0．053，0．059)。然而，延迟G-CSF治疗显示能够削弱即刻G-CSF治疗引起的左室负性重塑，左室游离壁厚度增加(P=0．143)，膨展指数减小(P=0．079)，存活心肌细胞横截面积减小(P＜0．05)；左室功能较即刻G-CSF治疗组明显改善，LVDP减小(P＜0．05)而±dP／dt_(max)增加(P＜0．05)。G-CSF联合AMD3100治疗组心脏功能较即刻G-CSF治疗组明显改善。②G-CSF单独治疗及G-CSF联合AMD3100治疗，可引起梗死区胶原成熟度明显降低(P＜0．05，vs 3m-saline组)，但不影响梗死区胶原沉积量。③G-CSF单独治疗及G-CSF联合AMD3100治疗，能够明显增加梗死区新生小动脉密度(P＜0．05，vs 3m-sham组)。
此外，G-CSF单独治疗及联合AMD3100治疗能够下调MMP-2／TIMP-2、MMP-9／TIMP-1比值，同时上调TGF-β_1、SDF-1和VEGF表达水平。
结论：在本研究中，G-CSF治疗并未改善心肌缺血／再灌注损伤后修复远期(3个月)左室的组织病理学改变和心功能。与延迟G-CSF治疗(再灌注后24小时)比较，即刻G-CSF治疗(再灌注后1小时)甚至导致更为严重的左室重塑，提示G-CSF的治疗时间窗对于左室创伤修复具有重要作用。此外，AMD3100的联合治疗削弱了G-CSF诱导的左室负性重塑，提示非CXCR4效应参与了心肌梗死后组织修复过程。
Background:Despite the fact that stem cell mobilization via granulocytecolony-stimulating factor (G-CSF) after myocardial infarction (MI) appears toimprove ventricular remodeling in some experimental and clinical reports,the effectsof G-CSF on post-infarct healing and related mechanisms remain controversial.G-CSF can promote mobilization of bone marrow stem cells into peripheral blood,thus facilitating the recruitment of CRCR4~+ cell into ischemic tissue by formingCXCR4/SDF-1 complex,which could be categorized CXCR4 mediated effects.Inaddition,other effects,such as direct action with G-CSF receptor on cardiomyocytesand subsequent activation of Jak2-Stat3 signal to inhibit apoptosis,could becategorized as non-CXCR4 mediated effects.In this study,we aimed to investigatethe effects of G-CSF on cardiac remodeling after experimental myocardial ischemiareperfusion with treatment of G-CSF and AMD3100 (CXCR4 antagonist) tosystematically evaluate the influence of G-CSF mediated CXCR4 effects andnon-CXCR4 effects on cardiac remodeling in the early and late phase of infarcthealing.
Materials and Methods:Rat model of myocardial ischemia reperfusion (I/R) wasestablished in 129 male Wistar rats.Survival animals were randomly divided intoimmediate treatment group (i.e.1 hour after repeffusion,I) or delayed treatmentgroup (i.e.24 hours after reperfusion,D).Each group was further divided into G-CSF(I-G and D-G) and G-CSF plus AMD3100 (CXCR-4 antagonist) (I-GA and D-GA)groups according different regiments of drug administration.7 days and 3 monthsafter I/R,rats were sacrificed and hearts were prepared separately for histologicalanalysis and protein extraction.Before scarification,left ventrioular (LV) functionwas assessed by LV catheterization via right carotid artery by Millar 2F pressurecatheter (SPR320) in all 3 months groups.Collagen deposition and maturation weredetermined by picrosirius-red stained heart tissue sections,under circularly polarizedlight.Arteriogenesis in the infarct and remote area was evaluated by FITC-labeled α-SMA immunofluorecent staining.Wheat germ agglutinin (WGA) staining wasperformed for determination of cross-sectional area (CSA) of viable cardiomyocytesin the septum.Gelatin zymography was used for determination of matrixmetalloproteinase-2 (MMP-2) and MMP-9 activity in the infarct area.The proteinabundance of MMP-2,MMP-9,TIMP-1,TIMP-2,transforming growth factorβ_1(TGF-β_1),stromal cell derived factor-1 (SDF-1) and vascular endothelial growthfactor (VEGF) was determined by western blot.
Results:7 days after I/R,rats treated with G-CSF plus AMD3100 co-administrationshowed higher mononuclear cells counts in peripheral blood compared with controlgroup (P＜0.05).There was a borderline difference in infarct size between immediateand delayed G-CSF treatment group (P=0.050).Arteriolar density within infarctregion in I/R groups increased significantly than that in sham group (P＜0.05).
3 months after I/R,①Immediate G-CSF treatment was associated with impairedLV remodeling compared with control group,as show by decreased LV free wall(P=0.056) and septum thickness (P=0.031),increased expansion index (P=0.056),increased infarct size (P=0.301,vs 3m-saline;P＜0.05,vs 7d-I-G),increased crosssectional area (CSA) of vital myocardiocytes (P＜0.05),and aggregated LV functionwith incareased LV diastolic pressure (LVDP) (P＜0.05,) and decreased±dP/dt_(max)(P=0.053 and 0.059,respectively).However,delayed G-CSF treatment resulted inimproved LV remodeling compared with immediate G-CSF treatment,as illustratedby decreased LV free wall thickness (P=0.143),decreased expansion index (P=0.079),decreased CSA of vital myocardioeytes (P＜0.05),and improved LV function withdecreased LVDP (P＜0.05) and increased±dP/dt_(max) (P＜0.05).Co-treatment withAMD3100 also exhibited better LV function than immediate G-CSF treatment withdecreased LVDP and (P＜0.05) and increased±dP/dt_(max) (P＜0.05).②Mobilization ofstern cells by G-CSF,and G-CSF plus AMD3100 could give rise to decreasedcollagen mutation (P＜0.05),but did not significantly influence the collagendeposition in the infarct area.③G-CSF,and G-CSF plus AMD3100 treatments wereassociated with increased arteriolar density.
In addition,G-CSF,and G-CSF plus AMD3100 administration associated with down-regulation of MMP-2/TIMP-2 and MMP-9/TIMP-1,and up-regulation ofTGF-β_1,SDF-1,and VEGF expression levels.
Conclusion:In the present long-term (3 months) experimental study,G-CSFtreatment is not associated beneficial effects on LV histopathological and mechanicalchanges after myocardial ischemia/reperfusion injury.Immediate G-CSF treatment (1hour after reperfusion) could result in more significantly worsened post-infarct LVremodeling,compared with delayed treatment (24 hours after reperfusion),whichindicates that the timing of G-CSF administration has a great impact on LV woundrepair.On the contrary,co-administration of AMD3100 may mitigate G-CSF inducedadverse post-infarct LV remodeling,implying a potential role of non-CXCR4 effectsin post-infarct healing process.
引文
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