title: Granulocyte colony-stimulating factor improves left ventricular function of doxorubicin-induced cardiomyopathy.
abstract: It is not well-known yet how granulocyte colony-stimulating factor (G-CSF) affects nonischemic cardiomyopathy, though its beneficial effects on acute myocardial infarction are well-established. We hypothesize that G-CSF beneficially might affect nonischemic cardiomyopathy through the direct cardioprotective effects. Here, we show that a single injection of doxorubicin (DOX, 15 mg/kg) induced left ventricular dilatation and dysfunction in mice within 2 weeks, and that these effects were significantly attenuated by human recombinant G-CSF (100 microg/kg/day for 5 days). G-CSF also protected hearts against DOX-induced cardiomyocyte atrophy/degeneration, fibrosis, inflammatory cell infiltration and down regulation of GATA-4 and sarcomeric proteins, myosin heavy chain, troponin I and desmin, both in vivo and in vitro. Cardiac cyclooxygenase-2 was upregulated and G-CSF receptor was downregulated in DOX-induced cardiomyopathy, but both of those effects were largely reversed by G-CSF. No DOX-induced apoptotic effects were seen, nor were there any changes in tumor necrosis factor-alpha or transforming growth factor-beta1 levels. Among downstream mediators of G-CSF receptor signaling, DOX-induced cardiomyopathy involved inactivation of extracellular signal-regulated protein kinase (ERK); the ERK inactivation was reversed by G-CSF. Inhibition of ERK activation, but not cyclooxygenase-2 inhibition, completely abolished beneficial effect of G-CSF on cardiac function. G-CSF did not promote differentiation of bone marrow cells into cardiomyocytes according to the experiment using green fluorescent protein-chimeric mice, and inhibition of CXCR4+ cell homing using AMD3100 did not diminish the effect of G-CSF. Finally, G-CSF was also effective when administered after cardiomyopathy was established. In conclusion, these findings imply the therapeutic usefulness of G-CSF mainly through restoring ERK activation against DOX-induced nonischemic cardiomyopathy.
authors.affiliation: Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Longhu
authors.initials: L
authors.lastname: Li
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.forename: Shusaku
authors.initials: S
authors.lastname: Miyata
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogino
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Munehiro
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000648:ultrastructure; D011994:Recombinant Proteins; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D004338:Drug Combinations; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases