Treatment with granulocyte colony-stimulating factor ameliorates chronic heart failure.
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.
Li
Yiwen
Y
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Takemura
Genzou
G
Okada
Hideshi
H
Miyata
Shusaku
S
Esaki
Masayasu
M
Maruyama
Rumi
R
Kanamori
Hiromitsu
H
Li
Longhu
L
Ogino
Atsushi
A
Misao
Yu
Y
Khai
Ngin C
NC
Mikami
Atsushi
A
Minatoguchi
Shinya
S
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002303:Cardiac Output, Low / Q000188:drug therapy*; D002908:Chronic Disease; D004797:Enzyme-Linked Immunosorbent Assay; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006321:Heart / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration
D016179:Granulocyte Colony-Stimulating Factor