Double-Edged Role of the CXCL12/CXCR4 Axis in Experimental Myocardial Infarction
Double-Edged Role of the CXCL12/CXCR4 Axis in Experimental Myocardial Infarction
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DOI：
10.1016/j.jacc.2011.08.033
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发表时间：
2011-11-29
影响因子：
24
通讯作者：
Weber, Christian
中科院分区：
文献类型：
--
作者：
Liehn, Elisa A.;Tuchscheerer, Nancy;Weber, Christian
目的探讨趋化因子受体CXCR 4在心肌梗死（MI）后重构中的内在功能。趋化因子CXCL 12通过募集血管生成细胞、改善新生血管形成和心功能参与MI后的保护和治疗性再生，但其受体CXCR 4的内源性作用尚不清楚。Langendoff灌注，超声心动图，定量免疫组化，流式细胞术，血管生成测定，心肌细胞analysis.Results 4周后，梗死面积减少Cxcr 4（+/-）小鼠与野生型小鼠相比，并在各自的骨髓嵌合体与对照组相比。这与炎性细胞募集改变、中性粒细胞含量降低、单核细胞浸润延迟以及Gr 1（低）相对于经典Gr 1（高）单核细胞的优势相关。Cxcr 4（+/-）小鼠心肌梗死后基础冠状动脉血流及其恢复受损，其原因是血管生成、心肌血管密度和内皮细胞计数减少。值得注意的是，与野生型小鼠相比，在Cxcr 4（+/-）小鼠中没有观察到心脏功能的差异。尽管血管生成缺陷，Cxcr 4（+/-）小鼠心脏在CXCL 12、血管内皮生长因子或凋亡相关基因表达方面没有差异。电镜观察发现CXCR 4（+/-）小鼠心脏内脂褐素样脂质积聚，脂质提取物分析检测到高水平的磷脂酰丝氨酸，其在体外保护心肌细胞免受缺氧stress.Conclusions CXCR 4在MI后内源性重构过程中起着至关重要的作用，有助于炎症/祖细胞募集和新生血管形成，而它的缺乏限制了梗塞面积并引起对缺氧应激的适应。在设计涉及CXCL 12/CXCR 4轴的治疗策略时，应仔细审查这一点。（J Am科尔心脏病学杂志2011;58：2415-23）（C）美国心脏病学会基金会2011年
Objectives Here we assess the intrinsic functions of the chemokine receptor CXCR4 in remodeling after myocardial infarction (MI) using Cxcr4 heterozygous (Cxcr(4+/-)) mice.Background Myocardial necrosis triggers complex remodeling and inflammatory changes. The chemokine CXCL12 has been implicated in protection and therapeutic regeneration after MI through recruiting angiogenic outgrowth cells, improving neovascularization and cardiac function, but the endogenous role of its receptor CXCR4 is unknown.Methods MI was induced by ligation of the left descending artery. Langendoff perfusion, echocardiography, quantitative immunohistochemistry, flow cytometry, angiogenesis assays, and cardiomyocyte analysis were performed.Results After 4 weeks, infarct size was reduced in Cxcr4(+/-) mice compared with wild-type mice and in respective bone marrow chimeras compared with controls. This was associated with altered inflammatory cell recruitment, decreased neutrophil content, delayed monocyte infiltration, and a predominance of Gr1(low) over classic Gr1(high) monocytes. Basal coronary flow and its recovery after MI were impaired in Cxcr4(+/-)mice, paralleled by reduced angiogenesis, myocardial vessel density, and endothelial cell count. Notably, no differences in cardiac function were seen in Cxcr4(+/-)mice compared with wild-type mice. Despite defective angiogenesis, Cxcr4(+/-) mouse hearts showed no difference in CXCL12, vascular endothelial growth factor or apoptosis-related gene expression. Electron microscopy revealed lipofuscin-like lipid accumulation in Cxcr4(+/-) mouse hearts and analysis of lipid extracts detected high levels of phosphatidylserine, which protect cardiomyocytes from hypoxic stress in vitro.Conclusions CXCR4 plays a crucial role in endogenous remodeling processes after MI, contributing to inflammatory/progenitor cell recruitment and neovascularization, whereas its deficiency limits infarct size and causes adaptation to hypoxic stress. This should be carefully scrutinized when devising therapeutic strategies involving the CXCL12/CXCR4 axis. (J Am Coll Cardiol 2011;58:2415-23) (C) 2011 by the American College of Cardiology Foundation