Treatment with granulocyte colony-stimulating factor ameliorates chronic heart failure
Treatment with granulocyte colony-stimulating factor ameliorates chronic heart failure
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DOI：
10.1038/labinvest.3700367
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发表时间：
2006-01-01
影响因子：
5
通讯作者：
Fujiwara, H
中科院分区：
文献类型：
--
作者：
Li, YW;Takemura, G;Fujiwara, H
慢性心力衰竭仍然是导致死亡的主要原因。尽管有报道称粒细胞集落刺激因子（G-CSF）在心肌梗死（MI）发病前或急性期给予对梗死后心脏重构和功能障碍有有益影响，但其对已建立的心力衰竭的影响尚不清楚。我们在这里表明，皮下注射G-CSF可以极大地改善由于大面积愈合的心肌梗死而导致的小鼠心力衰竭的功能。G-CSF将梗死疤痕的几何形状从细长变为短而厚，诱导存活的心肌细胞肥厚，并减少心肌纤维化。G-CSF受体的表达在衰竭心脏中得到证实，并在G-CSF治疗后上调。G-CSF处理还导致信号转导和转录激活因子-3的激活，并诱导GATA-4和各种肌肉合成蛋白，如肌球蛋白重链、肌钙蛋白I和desmin。在g - csf处理的心脏中，金属蛋白酶-2和-9的表达也增加，而肿瘤坏死因子- α、血管紧张素II型1受体（AT1）和转化生长因子- β 1的表达降低。虽然在g - csf处理的心脏中发现了Akt的活化，但血管密度没有变化，细胞凋亡也很少，无法发挥有意义的作用。在绿色荧光蛋白嵌合小鼠衰竭心脏中未发现骨髓来源的心肌细胞或血管细胞。最后，G-CSF对心功能的有益作用在停止治疗（2周）后仍持续很长时间。总的来说，这些发现表明G-CSF给药可能是治疗大面积心肌梗死后慢性心力衰竭的有效方法。
Chronic heart failure remains a leading cause of mortality. Although granulocyte colony-stimulating factor (G-CSF) is reported to have a beneficial affect on postinfarction cardiac remodeling and dysfunction when administered before the onset of or at the acute stage of myocardial infarction (MI), its effect on established heart failure is unknown. We show here that subcutaneous administration of G-CSF greatly improves the function of murine hearts failing due to a large, healed MI. G-CSF changed the geometry of the infarct scar from elongated and thin to short and thick, induced hypertrophy among surviving cardiomyocytes, and reduced myocardial fibrosis. Expression of G-CSF receptor was confirmed in failing hearts and was upregulated by G-CSF treatment. G-CSF treatment also led to activation of signal transducer and activator of transcription-3 and induction of GATA-4 and various sarcomeric proteins such as myosin heavy chain, troponin I and desmin. Expression of metalloproteinase-2 and -9 was also increased in G-CSF-treated hearts, while that of tumor necrosis factor-alpha, angiotensin II type 1 receptor (AT1) and transforming growth factor-beta 1 was reduced. Although activation of Akt was noted in G-CSF-treated hearts, vessel density was unchanged, and apoptosis was too rare to exert a meaningful effect. No bone marrow-derived cardiomyocytes or vascular cells were detected in the failing hearts of green fluorescent protein chimeric mice. Finally, beneficial effects of G-CSF on cardiac function were found persisting long after discontinuing the treatment (2 weeks). Collectively, these findings suggest G-CSF administration could be an effective approach to treating chronic heart failure following a large MI.