Abstract
BackgroundGranulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine, was recently used to treat patients of acute myocardial infarction with beneficial effect. However, controversy exists as some patients developed re-stenosis and worsened condition post G-CSF delivery. This study presents a new disease model to study G-CSF induced cardiac thrombosis and delineate its possible mechanism. We used iron loading to mimic condition of chronic cardiac dysfunction and apply G-CSF to mice to test our hypothesis.Methods and ResultsEleven out of fifteen iron and G-CSF treated mice (I+G) showed thrombi formation in the left ventricular chamber with impaired cardiac function. Histological analysis revealed endothelial fibrosis, increased macrophage infiltration and tissue factor expression in the I+G mice hearts. Simvastatin treatment to I+G mice attenuated their cardiac apoptosis, iron deposition, and abrogated thrombus formation by attenuating systemic inflammation and leukocytosis, which was likely due to the activation of pAKT activation. However, thrombosis in I+G mice could not be suppressed by platelet receptor inhibitor, tirofiban.ConclusionsOur disease model demonstrated that G-CSF induces cardiac thrombosis through an inflammation-thrombosis interaction and this can be attenuated via statin therapy. Present study provides a mechanism and potential therapy for G-CSF induced cardiac thrombosis.
Highlights
Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine, was recently used to treat patients of acute myocardial infarction with beneficial effect
Our disease model demonstrated that G-CSF induces cardiac thrombosis through an inflammationthrombosis interaction and this can be attenuated via statin therapy
Since chronic iron loading increases vascular oxidative stress and accelerate atherosclerosis [15,16,17]; we provided iron loading and G-CSF to mice to test our hypothesis by examining the incidence of cardiovascular thrombosis
Summary
Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine, was recently used to treat patients of acute myocardial infarction with beneficial effect. This study presents a new disease model to study G-CSF induced cardiac thrombosis and delineate its possible mechanism. Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine, induces mobilization of the hematopoietic stem cells from the bone marrow into the peripheral blood circulation. We showed that HMG-CoA reductase inhibitor, or statin therapy, could abrogate thrombus formation in I +G mice [18,19] Using this novel animal disease model, our objective was to elucidate the molecular mechanism of post G-CSF cardiac thrombosis and to investigate possible modalities for its treatment and prevention
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