Granulocyte colony-stimulating factor prevents reperfusion injury after heart preservation.
BACKGROUND
Heart transplantation is an accepted method of treatment for selected patients with end-stage heart disease. Making prolonged heart preservation safer will benefit patients awaiting heart transplantation. Granulocyte colony-stimulating factor (G-CSF) exhibited protective effects against myocardial ischemia-reperfusion injury mediated through the Janus kinase (Jak)/(signal transducer and activator of transcription (Stat) pathway. We examined whether pharmacologic preconditioning with G-CSF improves cardiac function after heart preservation.


METHODS
Male rats were divided into four groups: group A, saline injection; group B, G-CSF, 10 microg/kg; group C, G-CSF, 100 microg/kg; and group D, G-CSF, 100 microg/kg plus AG490 (a selective Jak2 inhibitor), 1 mg/kg. The G-CSF and AG490 were given intravenously for 3 consecutive days. Four hours after the final treatment, isolated rat hearts underwent 12 hours of hypothermic (4 degrees C) preservation, followed by 60 minutes of normothermic reperfusion.


RESULTS
Stat3 phosphorylation was observed in the heart at 15 minutes after G-CSF treatment in group C, but this was attenuated by additional treatment with AG 490 in group D. Compared with group A, group C exhibited significant recovery of left ventricular pressure, maximum positive rate of left ventricular developed pressure (Max dP/dt), and coronary flow (p < 0.05, respectively), as well as lower creatine phosphokinase leakage during reperfusion (p < 0.05). Group B and group D did not show significant hemodynamic recovery during reperfusion. In group C, increased Bcl-xL and decreased Bax expressions as well as decreased terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling (TUNEL)-positive cardiomyocytes were observed after reperfusion. Immunohistochemical examination showed significantly increased capillary density before hypothermic preservation in group C, but not in other groups.


CONCLUSIONS
Pharmacologic preconditioning with G-CSF protected hearts from prolonged hypothermic ischemia-reperfusion injury.
Higuchi
Takuya
T
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Yamauchi-Takihara
Keiko
K
Matsumiya
Goro
G
Fukushima
Norihide
N
Ichikawa
Hajime
H
Kuratani
Toru
T
Maehata
Yoshito
Y
Sawa
Yoshiki
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006334:Heart Function Tests; D016027:Heart Transplantation / Q000009:adverse effects / Q000379:methods; D006439:Hemodynamics / Q000502:physiology; D007036:Hypothermia, Induced / Q000379:methods*; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D019194:Ischemic Preconditioning / Q000379:methods; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009926:Organ Preservation / Q000379:methods*; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012680:Sensitivity and Specificity; D020032:Tyrphostins / Q000494:pharmacology*
D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D016179:Granulocyte Colony-Stimulating Factor