Role of Cardiac Myocyte CXCR4 Expression in Development and Left Ventricular Remodeling After Acute Myocardial Infarction
Role of Cardiac Myocyte CXCR4 Expression in Development and Left Ventricular Remodeling After Acute Myocardial Infarction
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DOI：
10.1161/circresaha.110.223289
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发表时间：
2010-09-03
影响因子：
20.1
通讯作者：
Penn, Marc S.
中科院分区：
文献类型：
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作者：
Agarwal, Udit;Ghalayini, Wael;Penn, Marc S.
理由：基质细胞衍生因子(SDF)-1/CXCR4轴在心脏发育过程中具有重要作用，并且已被证明是急性心肌梗死（AMI）和缺血性心肌病后优化心室重构的潜在治疗靶点。虽然是治疗靶点，但心肌细胞CXCR4 （CM-CXCR4）表达在心肌发生、心肌细胞存活和AMI后左室重构中的具体作用尚不清楚。目的：我们假设心肌细胞来源的CXCR4对心脏发育至关重要，但由于AMI后SDF-1的短暂表达和CM-CXCR4的延迟表达，它可能在成年期没有继发作用。为了解决这个问题，我们开发了先天性和条件CM-CXCR4（-/-）小鼠模型。方法与结果：在C57BL/6J背景下，将CXCR4（flox/flox）小鼠与MCM-Cre（+/-）小鼠和MLC2v-Cre（+/-）小鼠杂交，获得两株CM-CXCR4(flox/flox) MCM-Cre（+/-）和CXCR4(flox/flox)MLC2v-Cre（+/-）小鼠。研究表明，在MLC2v-Cre（+/-）小鼠中先天性重组和在MCM-Cre（+/-）小鼠中给予他莫昔芬后重组。令人惊讶的是，CXCR4(flox/flox)MLC2v-Cre（+/-）存活，心功能正常，无室间隔缺损迹象。AMI前2周用他莫昔芬治疗的CXCR4(flox/flox)MCM（+/-）在AMI后48小时心肌CXCR4表达降低90%。AMI后21天，超声心动图显示，无论Cre表达策略如何，CXCR4（flox/flox）小鼠与CM-CXCR4（-/-）小鼠在壁厚、左心室尺寸或射血分数（40.9 +/- 7.5% vs 34.4 +/- 2.6%）方面均无统计学差异。血管密度无差异（2369 +/- 131 vs 2471 +/- 126血管/mm）；观察AMI后21天CXCR4（flox/flox）与CM-CXCR4（-/-）小鼠)、梗死面积、胶原含量或非梗死区心肌细胞大小。结论：我们得出结论，心肌细胞衍生的CXCR4对心脏发育不是必需的，可能是因为SDF-1和CXCR4峰值的时间不匹配，在AMI后心室重构中没有主要作用。（Circ Res. 2010;107:667-676。）
Rationale: Stromal cell-derived factor (SDF)-1/CXCR4 axis has an instrumental role during cardiac development and has been shown to be a potential therapeutic target for optimizing ventricular remodeling after acute myocardial infarction (AMI) and in ischemic cardiomyopathy. Although a therapeutic target, the specific role of cardiac myocyte CXCR4 (CM-CXCR4) expression following cardiogenesis and survival of cardiac myocyte and left ventricular remodeling after AMI is unknown.Objective: We hypothesized that cardiac myocyte derived CXCR4 is critical for cardiac development, but it may have no role in adulthood secondary to the short transient expression of SDF-1 and the delayed expression of CM-CXCR4 following AMI. To address this issue, we developed congenital and conditional CM-CXCR4(-/-) mouse models.Methods and Results: Two strains of CM-CXCR4(flox/flox) mice were generated by crossing CXCR4(flox/flox) mice with MCM-Cre(+/-) mouse and MLC2v-Cre(+/-) mouse on the C57BL/6J background, yielding CXCR4(flox/flox) MCM-Cre(+/-) and CXCR4(flox/flox)MLC2v-Cre(+/-) mice. Studies demonstrated recombination in both models congenitally in the MLC2v-Cre(+/-) mice and following tamoxifen administration in the MCM-Cre(+/-) mice. Surprisingly the CXCR4(flox/flox)MLC2v-Cre(+/-) are viable, had normal cardiac function, and had no evidence of ventricular septal defect. CXCR4(flox/flox)MCM(+/-) treated with tamoxifen 2 weeks before AMI demonstrated 90% decrease in cardiac CXCR4 expression 48 hours after AMI. Twenty-one days post AMI, echocardiography revealed no statistically significant difference in the wall thickness, left ventricular dimensions or ejection fraction (40.9 +/- 7.5 versus 34.4 +/- 2.6%) in CXCR4(flox/flox) mice versus CM-CXCR4(-/-) mice regardless of strategy of Cre expression. No differences in vascular density (2369 +/- 131 versus 2471 +/- 126 vessels/mm(2); CXCR4(flox/flox) versus CM-CXCR4(-/-) mouse), infarct size, collagen content, or noninfarct zone cardiac myocyte size were observed 21 days after AMI.Conclusions: We conclude that cardiac myocyte-derived CXCR4 is not essential for cardiac development and, potentially because of the mismatch in timings of peaks of SDF-1 and CXCR4, has no major role in ventricular remodeling after AMI. (Circ Res. 2010;107:667-676.)