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Isolation of Functional Cardiac Immune Cells
Published on: December 5, 2011
Regression of cardiac hypertrophy by granulocyte colony-stimulating factor-stimulated interleukin-1β synthesis
Sebastian Szardien1, Holger M Nef, Sandra Voss
1Department of Cardiology, Kerckhoff Heart and Thorax Center, Benekestrasse 2-8, D-61231 Bad Nauheim, Germany.
Insights
Granulocyte colony-stimulating factor (G-CSF) treatment significantly improved cardiac function and reduced fibrosis after pressure unloading in a mouse model. This suggests G-CSF may be a potential therapy for heart failure post-aortic valve replacement.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Pharmacology
Background:
- Aortic stenosis leads to cardiac hypertrophy and fibrosis, persisting post-aortic valve replacement.
- Persistent myocardial fibrosis impairs cardiac function and increases mortality.
- Investigating G-CSF's role in cardiac remodeling after pressure unloading is crucial.
Purpose of the Study:
- To investigate the effects of granulocyte colony-stimulating factor (G-CSF) on cardiac remodeling after pressure unloading.
- To determine if G-CSF can beneficially influence cardiac hypertrophy and fibrosis.
- To explore the underlying mechanisms of G-CSF's action on cardiac fibrosis.
Main Methods:
- Aortic stenosis was induced in mice via transverse aortic constriction, followed by debanding to simulate aortic valve replacement.
- Mice received either G-CSF or saline treatment post-debanding.
- Cardiac function, fibrosis, neutrophil infiltration, and cytokine/matrix metalloproteinase expression were assessed.
Main Results:
- G-CSF treatment significantly improved systolic and diastolic cardiac function.
- Cardiac fibrosis, including collagen I and III deposition, was significantly reduced by G-CSF.
- G-CSF induced neutrophil infiltration and IL-1β release, which in turn activated MMP-2 and MMP-9 in fibroblasts, promoting fibrosis regression.
Conclusions:
- G-CSF treatment effectively improves cardiac function and promotes fibrosis regression post-pressure unloading.
- A novel mechanism involving G-CSF-induced sterile inflammation and subsequent matrix metalloproteinase activation is identified.
- G-CSF presents a potential therapeutic strategy for heart failure patients post-aortic valve replacement, warranting further research and clinical trials.
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.
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