Effects of CXCR4 Gene Transfer on Cardiac Function After Ischemia-Reperfusion Injury
Effects of CXCR4 Gene Transfer on Cardiac Function After Ischemia-Reperfusion Injury
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DOI：
10.2353/ajpath.2010.090451
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发表时间：
2010-04-01
影响因子：
6
通讯作者：
Tarzami, Sima T.
中科院分区：
文献类型：
--
作者：
Chen, Jiqiu;Chemaly, Elie;Tarzami, Sima T.
急性冠状动脉闭塞是西方世界的主要死亡原因。在闭塞的急性期期间，对于开发限制心肌梗死（MI）的程度的治疗存在未满足的需求。最近，研究人员集中在使用趋化因子CXCL 12，CXCR 4的唯一确定的配体，作为一种新的治疗方式，招募干细胞患有MI的个人。在这里，我们研究了通过基因转移过度表达CXCR 4对MI的影响。将携带CXCR 4基因的腺病毒注射到大鼠心脏中，然后结扎左冠状动脉前降支，再灌注24小时。心脏功能通过超声心动图结合2，3，5-三苯基四氮唑氯化物染色来测量MI大小。与对照组相比，接受Ad-CXCR 4的大鼠显示梗死面积增加（13.5% +/- 4.1%）和缩短分数降低（38% +/- 5%）。组织学分析显示，CXCL 12和肿瘤坏死因子-α在CXCR 4过表达心脏的缺血区域的表达显著增加。CXCR 4过表达与梗死心脏中炎性细胞流入增加和心肌细胞凋亡增强相关。这些数据表明，在我们的模型中，过表达CXCR 4似乎增强缺血/再灌注损伤，可能是由于增强炎症细胞的募集，增加肿瘤坏死因子或生产，并激活细胞死亡/凋亡途径。(Am J Pathol 2010，176：1705-1715; DOI：10.2353/ajpath.2010.090451）
Acute coronary occlusion is the leading cause of death in the Western world. There is an unmet need for the development of treatments to limit the extent of myocardial infarction (MI) during the acute phase of occlusion. Recently, investigators have focused on the use of a chemokine, CXCL12, the only identified ligand for CXCR4, as a new therapeutic modality to recruit stem cells to individuals suffering from MI. Here, we examined the effects of overexpression of CXCR4 by gene transfer on MI. Adenoviruses carrying the CXCR4 gene were injected into the rat heart one week before ligation of the left anterior descending coronary artery followed by 24 hours reperfusion. Cardiac function was assessed by echocardiography couple with 2,3,5-Triphenyltetrazolium chloride staining to measure MI size. In comparison with control groups, rats receiving Ad-CXCR4 displayed an increase in infarct area (13.5% +/- 4.1%) and decreased fractional shortening (38% +/- 5%). Histological analysis revealed a significant increase in CXCL12 and tumor necrosis factor-alpha expression in ischemic area of CXCR4 overexpressed hearts. CXCR4 overexpression was associated with increased influx of inflammatory cells and enhanced cardiomyocyte apoptosis in the infarcted heart. These data suggest that in our model overexpressing CXCR4 appears to enhance ischemia/reperfusion injury possibly due to enhanced recruitment of inflammatory cells, increased tumor necrosis factor-or production, and activation of cell death/apoptotic pathways. (Am J Pathol 2010, 176:1705-1715; DOI: 10.2353/ajpath.2010.090451)