Dokument

Summary:
Within the scope of this work two separate projects were investigated : the contribution of NOD-dependent microRNA regulation in endothelial cytokine expression and vascular inflammation and the role of NOD1 and NOD2 in atherogenesis and cholesterol metabolism. Both NOD1 and NOD2 receptors belong to the class of pattern recognition receptors responsible for pathogen sensing, which mediate a proinflammatory innate immune response upon their activation. Regarding the first project it was shown that NOD1 and NOD2 activation differentially regulates three different microRNAs in murine lung primary endothelial cells: miR-147-3p, miR-200a-3p and miR-298-5p. On the background of the current literature and in-silico analysis performed during this work, TNF-α and IL-6 were identified as potential target genes of miR-147-3p and miR-298-5p. By performing transfection experiments using mimics for both microRNAs TNF-α as well as IL-6 exhibited a diminished expression, indicating a microRNA-driven target gene regulation. Since miR-147-3p and miR-298-5p are downregulated after NOD-stimulation, these results point to an amplifying mechanism of NOD-dependent cytokine induction, an essential prerequisite of vascular inflammation. Within the second project it was demonstrated that deficiency of NOD1 and NOD2 results in reduced lipid and leukocyte accumulation in atherosclerotic plaques, which correlates with decreased plasma cholesterol. Potential causes of this Nod-deficient phenotype could be an enhanced hepatic cholesterol uptake, mediated by an increased expression of LRP1. Moreover, macrophages isolated from Nod-deficient mice showed reduced foam cell formation due to an increased ABCA1 and ABCG1 expression, thereby promoting reverse cholesterol transport. Finally, Nod-deficient mice showed increased cholesterol and coprostanol content in the cecum, which correlates with an elevated, even though not significant, relative abundance of the gut bacterium Eubacterium coprostanoligenes that metabolizes cholesterol to coprostanol. These results indicate a comprehensive interlinking role of NOD1 and NOD2, including microRNA-regulated vascular inflammation and metabolic processes affecting atherogenesis like cholesterol metabolism. These results identified NOD1 and NOD2 – at different levels – as comprehensive regulators in vascular inflammation and atherogenesis.

Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten