Antifibrotischer Einfluss von Granulozyten-Kolonie-stimulierendem Faktor auf myokardiale Zellen in-vitro

Beschreibung

Aortic stenosis causes cardiac hypertrophy and fibrosis. The changes often persist despite pressure unloading after aortic valve replacement. The appearance of myocardial fibrosis in particular leads to impaired cardiac function and increased mortality. Owing to previous observations it is well known, that the administration of G-CSF leads to an improvement of cardiac remodeling after pressure unloading. G-CSF is an hematopoietic cytokine which regulates the differentiation and survival of hematopoietic precursor cells from the bone marrow. Initially, it was thought that G-CSF acts by virtue of ist stem cell mobilizing and proliferating properties through stem cell mobilization and incorporation into the heart muscle. This could not be proved. In vivo experiments showed a decrease in myocardial fibrosis as well as an increased number of neutrophilic granulocytes after administration of G-CSF. Also, an increase in gene expression of MMP-2 and MMP-9 and IL-1β could be seen. MMP-2 and MMP-9 are proteolytic enzymes that are able to cleave collagens and thus counteract fibrosis. IL-1β is a proinflammatory cytokine which is secreted in inflammatory reactions of various cells, especially macrophages. In this work, the mode of action of G-CSF was investigated in vitro using cell culture experiments. Initially, a direct effect of G-CSF on cardiomyocytes, cardiac fibroblasts or neutrophilic granulocytes was suspected. Both MMP-2 and MMP-9 did not change significantly after direct incubation oft he cells with G-CSF. Unlike IL-1β, which was significantly increased at mRNA level after incubation of G-CSF with neutrophilic granulocytes. Furthermore, after incubation of cardiac fibroblasts with IL-1β, a significant increase in MMP-2 and MMP-9 at mRNA level was observed, thus explaining the decline in myocardial fibrosis observed in vitro. These observations suggest that the positive mode of action of G-CSF in myocardial fibrosis, for example in the context of aortic stenosis, may be due to an increased IL-1β synthesis oft he neutrophilic granulocytes. The thus released IL-1β leads in cardiac fibroblasts to increased production of MMP-2 and MMP-9 which cleave collagens and counteract a myocardial fibrosis resulting from aortic stenosis.

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Anne-Kathrin Weipert

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Antifibrose Granulozyten Herzerkrankungen

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