Abstract 15626: G-CSF-induced Regression Of Cardiac Hypertrophy Is Mediated By Selective Release Of Interleukin-1 Beta
Background: Aortic stenosis causes cardiac fibrosis, which often persists despite pressure unloading after aortic valve replacement. Therefore, we investigated the effects and molecular mechanisms of the granulocyte colony-stimulating factor (G-CSF) in a mouse model that closely mimicks aortic stenosis and subsequent aortic valve replacement.
Methods: Left ventricular hypertrophy was induced by transverse aortic constriction (TAC) in C57bl6-mice (n=64) followed by debanding. A subgroup (n=20) were sublethally irradiated (11 Gy) three months prior to TAC followed by bone marrow transplantation using eGFP-transgenic donor mice. After debanding, mice received G-CSF for one week. Functional parameters were measured by echocardiography. Morphological parameters were assessed immunohistochemically. Cell culture experiments were performed to investigate direct effects of G-CSF.
Results: G-CSF treatment improved systolic (EF 72.34±1.17% vs. 61.41±1.56%, p<0.001) and diastolic function (E/E’ 26.0±1.0 vs. 32.6±0.8, p<0.05) compared to control. Furthermore, cardiac fibrosis was 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 bone marrow cells could be excluded. However, a considerable infiltration of macrophages and neutrophils was observed in G-CSF-treated mice. This sterile inflammation was accompanied by a selective release of interleukin-1 beta (IL-1b) in the absence of other proinflammatory cytokines. In vitro experiments confirmed an increased expression of Il-1b in neutrophils after G-CSF treatment (p<0.01). IL-1b directly induced the expression of the gelatinases MMP-2 and MMP-9 in cardiac fibroblasts (p<0.01) thereby providing the regression of cardiac fibrosis.
Conclusion: G-CSF treatment improves cardiac function and leads to the regression of myocardial fibrosis after pressure unloading. These findings reveal a previously unknown mechanism of fibrosis regression and provide a new pharmacological treatment approach for patients suffering from congestive heart failure after aortic valve replacement.
- © 2011 by American Heart Association, Inc.