Regression of cardiac hypertrophy by granulocyte colony-stimulating factor-stimulated interleukin-1β synthesis
| Autor: | Christian W. Hamm, Christian Troidl, Kathrin Kimmich, Andreas Rolf, Albrecht Elsässer, Baktybek Kojonazarov, Ralph T. Schermuly, Katharina Mayer, Sawa Kostin, Johannes Rixe, Kerstin Troidl, Sebastian Szardien, Jedrzej Hoffmann, Holger Nef, Helge Möllmann, Christoph Liebetrau, Maximilian Rauch, Sandra Voss |
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| Rok vydání: | 2011 |
| Předmět: |
Cardiac function curve
medicine.medical_specialty Cardiac fibrosis Interleukin-1beta Bone Marrow Cells Left ventricular hypertrophy Mice Aortic valve replacement Internal medicine Granulocyte Colony-Stimulating Factor medicine Animals Systole Aorta Ejection fraction Ventricular Remodeling business.industry Myocardium Stroke Volume Aortic Valve Stenosis medicine.disease Constriction Fibrosis Up-Regulation Mice Inbred C57BL Aortic valve stenosis Heart failure Cell Transdifferentiation Cardiology Female Hypertrophy Left Ventricular Cardiology and Cardiovascular Medicine business |
| Zdroj: | European Heart Journal. 33:595-605 |
| ISSN: | 1522-9645 0195-668X |
| DOI: | 10.1093/eurheartj/ehr434 |
| Popis: | Aims Aortic stenosis causes cardiac hypertrophy and fibrosis, which often persists despite pressure unloading after aortic valve replacement. The persistence of myocardial fibrosis in particular leads to impaired cardiac function and increased mortality. We investigated whether granulocyte colony-stimulating factor (G-CSF) beneficially influences cardiac remodelling after pressure unloading. Methods and results Left ventricular hypertrophy was induced by transverse aortic constriction in C57bl6 mice followed by debanding after 8 weeks. This model closely mimics aortic stenosis and subsequent aortic valve replacement. After debanding, mice were treated with either G-CSF or saline injection. Granulocyte colony-stimulating factor treatment significantly improved systolic (ejection fraction 70.48 ± 1.17 vs. 58.41 ± 1.56%, P < 0.001) and diastolic ( E / E ′ 26.0 ± 1.0 vs. 32.6 ± 0.8, P < 0.05) function. Furthermore, cardiac fibrosis was significantly reduced in G-CSF-treated mice (collagen-I area fraction 7.96 ± 0.47 vs. 11.64 ± 1.22%, P < 0.05; collagen-III area fraction 10.73 ± 0.99 vs. 18.46 ± 0.71%, P < 0.001). Direct effects of G-CSF on cardiac fibroblasts or a relevant transdifferentiation of mobilized bone marrow cells could be excluded. However, a considerable infiltration of neutrophils was observed in G-CSF-treated mice. This sterile inflammation was accompanied by a selective release of interleukin-1 β (IL-1β) in the absence of other proinflammatory cytokines. In vitro experiments confirmed an increased expression of IL-1β in neutrophils after G-CSF treatment. Interleukin-1β directly induced the expression of the gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9 in cardiac fibroblasts thereby providing the regression of cardiac fibrosis. Conclusion Granulocyte colony-stimulating factor treatment improves the cardiac function and leads to the regression of myocardial fibrosis after pressure unloading. These findings reveal a previously unknown mechanism of fibrosis regression. Granulocyte colony-stimulating factor might be a potential pharmacological treatment approach for patients suffering from congestive heart failure after aortic valve replacement, although further basic research and clinical trials are required in order to prove beneficial effects of G-CSF in the human organism. |
| Databáze: | OpenAIRE |
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