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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/H823    most recent 00774.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Hiraumi, Y. Articles by Adachi, S. Search for Related Content PubMed PubMed Citation Articles by Hiraumi, Y. Articles by Adachi, S.

Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury

¹Department of Pediatrics and ⁴Department of Pathology and Biology of Disease, Graduate School of Medicine, Kyoto University, Kyoto; and ²Department of Cardiovascular Medicine and ³Department of Transfusion and Cell Therapy, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan

Submitted 25 July 2008 ; accepted in final form 4 January 2009

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.

doxorubicin; mitochondria; cardiac diastolic function; oxygen consumption

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