Li Yiwen, Takemura Genzou, Okada Hideshi, Miyata Shusaku, Esaki Masayasu, Maruyama Rumi, Kanamori Hiromitsu, Li Longhu, Ogino Atsushi, Misao Yu, Khai Ngin C, Mikami Atsushi, Minatoguchi Shinya, Fujiwara Takako, Fujiwara Hisayoshi
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Lab Invest. 2006 Jan;86(1):32-44. doi: 10.1038/labinvest.3700367.
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-beta1 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.
慢性心力衰竭仍然是主要的死亡原因。尽管据报道，粒细胞集落刺激因子（G-CSF）在心肌梗死（MI）发作前或急性期给药时，对梗死后心脏重塑和功能障碍有有益影响，但其对已确诊心力衰竭的影响尚不清楚。我们在此表明，皮下注射G-CSF可显著改善因大面积陈旧性心肌梗死而衰竭的小鼠心脏功能。G-CSF使梗死瘢痕的形态从细长变薄变为短粗，诱导存活心肌细胞肥大，并减少心肌纤维化。在衰竭心脏中证实了G-CSF受体的表达，且G-CSF治疗使其上调。G-CSF治疗还导致信号转导和转录激活因子3的激活以及GATA-4和各种肌节蛋白如肌球蛋白重链、肌钙蛋白I和结蛋白的诱导。在G-CSF治疗的心脏中，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 1型受体（AT1）和转化生长因子-β1的表达则降低。尽管在G-CSF治疗的心脏中观察到Akt的激活，但血管密度未改变，且凋亡极少，无法产生有意义的影响。在绿色荧光蛋白嵌合小鼠的衰竭心脏中未检测到骨髓来源的心肌细胞或血管细胞。最后，发现G-CSF对心脏功能的有益作用在停药后很长时间（2周）仍持续存在。总的来说，这些发现表明，给予G-CSF可能是治疗大面积心肌梗死后慢性心力衰竭的有效方法。
