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Published on: May 28, 2019
Granulocyte colony-stimulating factor prevents reperfusion injury after heart preservation
Takuya Higuchi1, Keiko Yamauchi-Takihara, Goro Matsumiya
1Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Insights
Granulocyte colony-stimulating factor (G-CSF) preconditioning significantly improved heart function and reduced injury after prolonged preservation. This protective effect was mediated via the Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway.
Area of Science:
- Cardiology
- Regenerative Medicine
- Biochemistry
Background:
- Heart transplantation is a vital treatment for end-stage heart disease.
- Enhancing prolonged heart preservation is crucial for transplant recipients.
- Granulocyte colony-stimulating factor (G-CSF) shows promise in mitigating myocardial ischemia-reperfusion injury via the Jak/Stat pathway.
Purpose of the Study:
- To investigate the efficacy of pharmacologic preconditioning with G-CSF in improving cardiac function following prolonged heart preservation.
- To explore the role of the Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway in G-CSF-mediated cardioprotection.
Main Methods:
- Male rats were divided into four groups, receiving saline, varying doses of G-CSF, or G-CSF with a Jak2 inhibitor (AG490).
- Hearts underwent 12 hours of hypothermic preservation followed by 60 minutes of normothermic reperfusion.
- Cardiac function, biochemical markers, and cellular apoptosis were assessed post-reperfusion.
Main Results:
- G-CSF (100 microg/kg) significantly improved left ventricular pressure, Max dP/dt, and coronary flow, while reducing creatine phosphokinase leakage.
- G-CSF treatment led to increased Bcl-xL and decreased Bax expression, with fewer TUNEL-positive cardiomyocytes.
- Increased capillary density was observed in hearts preconditioned with G-CSF before preservation.
Conclusions:
- Pharmacologic preconditioning with G-CSF effectively protects the heart against prolonged hypothermic ischemia-reperfusion injury.
- The protective mechanisms involve modulation of apoptosis and enhancement of vascularity.
- G-CSF represents a potential therapeutic strategy to improve outcomes in heart transplantation.
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.
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