title: Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury.
abstract: Although granulocyte colony-stimulating factor (G-CSF) reportedly plays a cardioprotective role in several models of cardiac injury, clinical use of this drug in cardiac patients has been controversial. Here, we tested, in vivo and in vitro, the effect of G-CSF on cardiac mitochondria, which play a key role in determining cardiac cellular fate and function. Mild stimulation of C57/BL6 mice with doxorubicin (Dox) did not induce cardiac apoptosis or fibrosis but did induce damage to mitochondrial organization of the myocardium as observed through an electron microscope. Cardiac catheterization and echocardiography revealed that Dox did not alter cardiac systolic function or left ventricular size but did reduce diastolic function, an early sign of cardiac damage. Treatment with G-CSF attenuated significantly the damage to mitochondrial organization and rescued diastolic function. In an in vitro model for rat neonatal cardiomyocytes, a subapoptotic dose of Dox induced severe mitochondrial damage, including marked swelling of the cardiac mitochondria and/or decreased mitochondrial membrane potential. These mitochondrial changes were completely blocked by pretreatment with G-CSF. In addition, G-CSF dramatically improved ATP generation, which rescued Dox-impaired mitochondrial electron transport and oxygen consumption mainly through complex IV. These findings clearly indicate that G-CSF protects cardiac mitochondria, which are key organelles in the determination of cardiac cellular fate, in the early phase of cardiac injury.
authors.affiliation: Dept. of Pediatrics, Graduate School of Medicine, Kyoto Univ., Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Hiraumi
authors.forename: Eri
authors.initials: E
authors.lastname: Iwai-Kanai
authors.forename: Shiro
authors.initials: S
authors.lastname: Baba
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yui
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kamitsuji
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mizushima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsubara
authors.forename: Motonobu
authors.initials: M
authors.lastname: Watanabe
authors.forename: Ken-Ichirou
authors.initials: K
authors.lastname: Watanabe
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D006328:Cardiac Catheterization; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin; D004452:Echocardiography; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects; D007279:Injections, Subcutaneous; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV