BMP10 is a cardiac specific member of the TGF beta superfamily and the expression of this cytokine is limited to the right atrium of the healthy heart. In the work presented here, I attempted to unveil the function of BMP10 in the pathological adult heart.
RESULTS:
1. During embryonic heart development BMP10 expression was found in the trabeculated myocardial layer and BMP10 protein was observed additionally in the outflow tract, the compacted heart wall and the epicardial layer.
2. BMP10 in the healthy adult heart is expressed in the right atrium and after secretion binds to the membrane of both atrial cardiomyocytes and interstitial cells. Moreover, expression and binding of this protein was observed in the tricuspid valve and cells adjacent to the arteries in the upper atrial area of the heart.
3. The murine models used in this study represent the dilated and hypertrophic type of cardiomyopathy and exhibit different degrees of cardiac dysfunction characterized by changes in myocardial volume and reduced ejection fraction. Interstitial and replacement fibrosis, cardiomyocyte hypertrophy, myofiber disarray and cell death in respect to necrosis and apoptosis were detected but the degree of structural changes was different in all models. The number of apoptotic or necrotic cells was very low.
4. In diseased hearts two types of qualitative BMP10 distribution changes were found. The subcellular localization of BMP10 in cells of the right atrium was changed. In addition, BMP10 was re-expressed in ventricular cells.
5. In Desmin knock-out and in doxorubicin induced dilated cardiomyopathy upregulation of the BMP10 expression was found, while quantification of BMP10 in MnSOD heterozygous and isoproterenol treated mouse heart revealed its downregulation. These variations in BMP10 quantity were monitored at the RNA and protein level. The number of BMP10 positive cells in the ventricles of pathological hearts is low, and therefore quantitative changes represent most probably the deregulation of BMP10 expression in the right atrium.
6. Ventricular cells ectopically expressing BMP10 in pathological hearts are Sca1pos. and show signs of proliferation. Characterization of the ventricular BMP10pos. cells revealed that they constitute a heterogeneous population of cells often expressing endothelial and smooth muscle cell markers, but never cardiomyocyte specific genes. BMP10 is expressed, however, by embryonic and atrial cardiomyocytes.
7. BMP10 effects are dependent on the differentially expressed receptors in various cell lines. The effect of BMP10 in C2C12 cells is limited to the induction of osteoblast differentiation. In contrast, BMP10 induced multipotent mesenchymal 10T1/2 embryonic fibroblasts, adult bone marrow mesenchymal stem cells and in non-cardiomyocytes isolated from the adult mouse heart to express smooth muscle, endothelial and pericyte markers. Moreover, cells expressing these markers are able to form 3D tube-like structures indicating a possible role of BMP10 in angiogenesis.
CONCLUSION:On the basis of these results it can be concluded that BMP10 acts in an autocrine and paracrine fashion. As expression and localization of BMP10 changes dramatically even when the pathological changes are still moderate, BMP10 may play an important role in the disease process of dilated and hypertrophic cardiomyopathy. In cardiomyopathic hearts ventricular BMP10pos. cells seem to originate from cardiac Sca1 progenitors and it might be concluded that BMP10 induces their proliferation and differentiation. In addition, cell culture experiments show that BMP10 induced differentiation of mesenchymal cells to endothelial, smooth muscle cells and pericytes leading to the assembly of tube-like structures. BMP10 may play a protective role in the cardiomyopathies studied here by stimulating the development of the cardiac microvasculature including capillaries, arterioles and small arteries. This process might result in an inhibition or at least a delay of adverse remodeling of the heart, which is part of an important adaptive process to cardiac diseases.
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