Key Laboratory of Remodeling-Related Cardiovascular Diseases, Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Ministry of Education, Beijing, China.
Am J Hypertens. 2013 Oct;26(10):1224-33. doi: 10.1093/ajh/hpt095. Epub 2013 Jun 12.
Granulocyte colony stimulating factor (G-CSF) is a key mediator of neutrophil infiltration and is profibrotic in the liver, lung, and infarcted heart, but its roles in angiotensin II (Ang II)-induced hypertension and cardiac remodeling have not been fully determined. Thus, we sought to investigate the causal relation of G-CSF to neutrophil recruitment and cardiac fibrosis in C57BL/6J mice.
Hypertension and cardiac fibrosis were induced in wild-type (WT) mice receiving continuous infusion of Ang II (1,500ng/kg/min). After 7 days, heart sections were stained with hematoxylin and eosin, Masson's trichrome, and immunohistochemistry. The mRNA expression of cytokines was detected by real-time polymerase chain reaction analysis. The protein levels were measured by Western blot analysis.
After Ang II infusion, myocardial G-CSF expression was significantly elevated in the hearts. Moreover, WT mice exhibited increased blood pressure, marked neutrophil accumulation, proinflammatory cytokine expression, reactive oxygen species production, and cardiac fibrosis after 7 days of Ang II infusion. However, administration of anti-G-CSF neutralizing antibody, but not with control immunoglobulin G, significantly attenuated these effects. In addition, neutralizing G-CSF antibody reversed Ang II-induced activation of ERK1/2, STAT3, and AKT signaling pathways in the hearts.
This study demonstrates that G-CSF plays a critical role in hypertension and cardiac fibrosis and targeting this cytokine may be a novel therapeutic strategy to ameliorate hypertensive heart disease.
粒细胞集落刺激因子（G-CSF）是中性粒细胞浸润的关键介质，在肝脏、肺部和梗死心脏中具有成纤维作用，但它在血管紧张素 II（Ang II）诱导的高血压和心脏重构中的作用尚未完全确定。因此，我们试图研究 G-CSF 与 C57BL/6J 小鼠中性粒细胞募集和心脏纤维化之间的因果关系。
在接受 Ang II（1500ng/kg/min）持续输注的野生型（WT）小鼠中诱导高血压和心脏纤维化。7 天后，用苏木精和伊红、马松三色和免疫组织化学染色心脏切片。通过实时聚合酶链反应分析检测细胞因子的 mRNA 表达。通过 Western blot 分析测量蛋白质水平。
Ang II 输注后，心肌 G-CSF 表达在心脏中明显升高。此外，WT 小鼠在 Ang II 输注 7 天后表现出血压升高、明显的中性粒细胞积聚、促炎细胞因子表达、活性氧产生和心脏纤维化。然而，给予抗 G-CSF 中和抗体，但不是对照免疫球蛋白 G，可显著减弱这些作用。此外，中和 G-CSF 抗体逆转了 Ang II 诱导的心脏中 ERK1/2、STAT3 和 AKT 信号通路的激活。
这项研究表明，G-CSF 在高血压和心脏纤维化中起关键作用，靶向这种细胞因子可能是改善高血压性心脏病的一种新的治疗策略。
