CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism.
CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism.
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DOI：
10.1161/circulationaha.112.099242
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发表时间：
2013-01-01
期刊：
影响因子：
37.8
通讯作者：
Losordo DW
中科院分区：
文献类型：
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作者：
Jujo K;Ii M;Sekiguchi H;Klyachko E;Misener S;Tanaka T;Tongers J;Roncalli J;Renault MA;Thorne T;Ito A;Clarke T;Kamide C;Tsurumi Y;Hagiwara N;Qin G;Asahi M;Losordo DW
CXC趋化因子受体4（CXCR 4）调节干/祖细胞在骨髓（BM）中的保留，并且CXCR 4拮抗剂AMD 3100通过将干/祖细胞从BM动员到外周血来改善从冠状动脉结扎损伤的恢复。因此，我们研究了AMD 3100是否也能改善缺血再灌注（IR）损伤的恢复，IR损伤更接近于患者的心肌梗死，因为血流只是暂时受阻。IR损伤后，小鼠单次皮下注射AMD 3100（5 mg/kg）或生理盐水。3天后，AMD 3100处理小鼠的梗死面积/风险面积比的组织学测量值小于生理盐水处理小鼠，第4周时AMD 3100处理小鼠的左心室功能超声心动图测量值更大。CXCR 4+细胞在两组中均动员了1天，但在AMD 3100处理的小鼠中，sca 1 +/flk 1+细胞的动员持续了7天，而盐水处理的小鼠仅动员了1天。AMD 3100上调内皮型一氧化氮合酶（eNOS）和eNOS信号传导的两个靶点基质金属蛋白酶9和可溶性Kit配体的BM水平。此外，BM eNOS表达的丧失消除了AMD 3100对sca 1 +/flk 1+细胞动员的益处，而不改变CXCR 4+细胞的动员，并且在移植了野生型小鼠BM的eNOS敲除小鼠中保留了AMD 3100的心脏保护作用，但在移植了eNOS敲除BM的野生型小鼠中则没有。AMD 3100促进BM祖细胞动员并改善IR损伤的恢复，这些益处似乎是通过AMD 3100和BM eNOS表达之间先前未确定的联系而发生的。
CXC-chemokine receptor 4 (CXCR4) regulates the retention of stem/progenitor cells in the bone marrow (BM), and the CXCR4 antagonist AMD3100 improves recovery from coronary-ligation injury by mobilizing stem/progenitor cells from the BM to the peripheral blood. Thus, we investigated whether AMD3100 also improves recovery from ischemia-reperfusion (IR) injury, which more closely mimics myocardial infarction in patients, because blood flow is only temporarily obstructed. Mice were treated with single subcutaneous injections of AMD3100 (5 mg/kg) or saline after IR injury. Three days later, histological measurements of the infarct-area/area-at-risk ratio were smaller in AMD3100-treated mice than in mice administered saline, and echocardiographic measurements of left-ventricular function were greater in the AMD3100-treated mice at week 4. CXCR4+ cells were mobilized for just 1 day in both groups, but the mobilization of sca1+/flk1+ cells endured for 7days in AMD3100-treated mice compared to just 1 day in the saline-treated mice. AMD3100 upregulated BM levels of endothelial nitric oxide synthase (eNOS) and two targets of eNOS signaling, matrix-metalloproteinase 9 and soluble Kit ligand. Furthermore, the loss of BM eNOS expression abolished the benefit of AMD3100 on sca1+/flk1+ cell mobilization without altering the mobilization of CXCR4+ cells, and the cardioprotective effects of AMD3100 were retained in eNOS-knockout mice that had been transplanted with BM from wild-type mice, but not in wild-type mice with eNOS-knockout BM. AMD3100 prolongs BM progenitor mobilization and improves recovery from IR injury, and these benefits appear to occur through a previously unidentified link between AMD3100 and BM eNOS expression.