MikroRNA-146a-basierte Mechanismen vaskulärer Fibrose im Kontext der arteriellen Gefäßversteifung
MicroRNA-146a-based mechanisms of vascular fibrosis in arterial stiffening
Dissertation
Datum der mündl. Prüfung:2022-10-11
Erschienen:2022-10-05
Betreuer:Dr. Uwe Raaz
Gutachter:Dr. Uwe Raaz
Gutachter:Prof. Dr. Thorsten Roland Döppner
Förderer:DZHK e.V. (Promotionsstipendium WS16/17)
Dateien
Name:14_Dissertation Karin Mattern_SUB.pdf
Size:4.31Mb
Format:PDF
Description:Dissertationsschrift
Zusammenfassung
Englisch
Age-related arterial stiffening is both a serious cardiovascular disease and a risk factor in its own for other cardiovascular diseases. The underlying pathological mechanisms are the subject of current research. In particular, changes in the extracellular matrix of the aorta due to increased collagen synthesis or increased elastin fragmentation seem to be crucial. There is evidence that increased TGF-β1/SMAD3 signaling can trigger vascular fibrosis. Furthermore, collagen crosslinks of the HP type are incresased in fibrotic tissue. MiRs are post-transcriptional regulators that can regulate entire gene networks. MiR-146a has already been described as a protective regulator of inflammatory and fibrogenic processes. Furthermore, miR-146a could be measured in the blood of patients with increased arterial stiffness. SMAD3 has already been described as a target gene of miR-146a. It has also already been shown that SMAD3 acts as a transcription factor for the gene PLOD2, which is crucial for the development of HP. The aim of the present work was to investigate the influence of miR-146a on the mechanism of increased collagen synthesis in the context of age-related arterial stiffening. The results showed that miR-146a is significantly upregulated in both old murine aortas and on rigid cell culture plates. The genes SMAD3 and PLOD2 were significantly down-regulated after transfection of miR-146a mimic and significantly up-regulated after transfection of miR-146a inhibitor. However, the results of the experiment with siRNA for SMAD3 were not significant. The Scar-in-a-jar assay showed that the miR-146a mimic decreased the synthesis of collagen and the miR-146a inhibitor increased the synthesis. The present results indicate that miR-146a has a protective effect on the development of vascular fibrosis. The regulation could take place via the TGF-β1/SMAD3 signaling pathway and via the increased formation of crosslinks by LH2 and its gene PLOD2. The collected data show for the first time that miR-146a as an important regulator of vascular fibrosis in the context of age-related arterial stiffening. MiR-146a is therefore a promising target for novel miR-based therapeutic approaches to arterial stiffness.
Keywords: arterial stiffness; micro-RNA; SMAD3; PLOD2