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  • Another interesting aspect of neutralizing


    Another interesting aspect of neutralizing AP-1 is the inhibition of interactions between AP-1 and Smad proteins, which synergize to activate the TGF-β1-responsive genes involved in hypertrophic growth of the heart muscle and in the development of cardiac fibrosis. Through preventing AP-1 activation, we are not only able to reduce MMP expression and subsequently activity but may also achieve synergistic effects to treat MFS symptoms. By using fluorescent-marked dODNs, we could show that these molecules are able to pass the endothelial barrier and reach the smooth muscle cells in the aortic media of Marfan, but not of wild-type mice. In wild-type mice, the endothelial cell layer represents a major barrier site to the passive movement of small molecules, as already shown previously in native hearts perfused with fluorescent-dye-labeled dODN and grafts incubated with fluorescent albumin. Moreover, the immunohistological ZO-1 and occludine staining suggest that mgR/mgR mice have a leakage in endothelial barrier function within the intercellular boundaries, as published recently. This is a prerequisite for understanding the effectiveness of dODN in Marfan Hydroxysafflor yellow A and may also explain why the migration of immunological cells in AP-1 dODN grafts is reduced. Guo et al. demonstrated that aortic extracts from mgR/mgR mice were able to stimulate macrophage chemotaxis by interaction with elastin-binding protein and showed that fibrillin-1 fragments are capable of chemotactic stimulatory activity. These findings are in line with the observation that patients with progressive aortic disease showed higher levels of macrophage colony stimulating factor (M-CSF) in the blood. It has been demonstrated previously that M-CSF gene expression is mediated by transcription factors like AP-1. The method of ex vivo incubation of the descending thoracic aorta and re-implantation into the infrarenal abdominal aorta of genetically identical mice has been previously described. Using this approach by incubation with AP-1 consensus dODN of the aortic grafts, we could demonstrate a significant reduction of elastolysis. Moreover, the neutralization resulted not only in a reduced elastolysis but also in a reduced MMP activity. The modification of our decoy structure into a hairpin molecule could enable possible catheter-based applications or a systemic application. Miyake et al. already described a systemic approach using chimeric ribbon-type decoy ODNs against nuclear factor-κB for successful prevention of abdominal aneurysm formation in a rat model.
    Materials and Methods
    Author Contributions
    Conflicts of Interest
    Acknowledgments This work was supported by the B. Braun Foundation, Melsungen, Germany, and in part by a grant of the German state of Baden-Württemberg (M.K.). We are indebted to Antje Weber and Franziska Mohr for expert technical assistance.
    Introduction The three isoenzymes of the Raf protein kinase family, Raf-1, A-Raf and B-Raf, are cytosolic serine/threonine protein kinases with a high degree of sequence similarity. The enzymes have a modular structure, encompassing three domains: The N-terminal CR1 domain with two Ras binding domains is required for binding to activated Ras-GTP, the serine and threonine-rich CR2 domain negatively regulates the biological activity of Raf, and the CR3 domain is the catalytic protein kinase domain. Activated Raf phosphorylates and activates the mitogen activated protein (MAP) kinase MEK which in turn phosphorylates and activates the MAP kinases extracellular signal-regulated protein kinases ERK1 and ERK2. Raf enzymes have a narrow substrate specificity, with MEK as the best-known substrate (O'Neill and Kolch, 2004, Wellbock et al., 2004). A microarray analysis confirmed that the transcriptional response to Raf almost completely depends on MEK activation (Schulze et al., 2004). Accordingly, many functions attributed to Raf activation are executed by the subsequent activation of MEK and ERK1/2. In insulinoma cells, ERK1/2 translocates into the nucleus in response to glucose stimulation (Benes et al., 1998) and changes the gene expression pattern of the cells via phosphorylation of gene regulatory proteins.