Rolle des Wachstums-Differenzierungs-Faktors-15 (GDF-15) bei der Regulation von Autophagie bzw. Apoptose und möglicher Einfluss auf die Plaquegröße bei cholesterinreich gefütterten ApoE-/--Mäusen
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Date
2025-10-21
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Philipps-Universität Marburg
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Abstract
Cardiovascular diseases are one of the most common causes of death worldwide, accounting for more than 30% of all deaths. The primary cause of cardiovascular diseases are atherosclerotic changes. Atherosclerosis is a degenerative disease associated with a chronic inflammatory reaction with lipid deposits and accumulation of extracellular matrix in the arterial walls. Growth differentiation factor-15 [GDF-15] has been the subject of intensive research for several years and is one of the most important and currently much-studied actors in the pathophysiology of atherosclerosis (69 publications from 2020-2025, Pubmed.com). Nevertheless, the effects of GDF-15 and its receptors in the organism still offer many open research questions. GDF-15 is widely distributed in adult tissues and is mainly expressed in epithelial cells, macrophages, smooth muscle cells and adipocytes. Its production is regulated by various forms of oxidative stress, inflammation and cell ageing. Autophagy and apoptosis play a crucial role in the development of atherosclerotic plaques, as dysfunction can lead to the expansion and instability of atherosclerotic plaques. Previous in vitro studies have shown that GDF-15 is an important player in the process of apoptosis and autophagy. Therefore, the present study investigates the effects of GDF-15 deficiency on luminal stenosis in the context of autophagy and apoptosis processes in the atherosclerotic brachiocephalic trunk [TB] of ApoE-/--mice.
GDF-15 knockout/lacZ knockin (GDF15-/-) mice were crossed with ApoE-/--mice to generate GDF15-/-/ApoE-/--mice. Male homozygous GDF-15-/-/ApoE-/-- and ApoE-/--mice were fed a cholesterol-enriched diet from 10 weeks of age for a period of 20 weeks. The body measurements and blood lipid values of the two mouse genotypes were then determined and the atherosclerotic brachiocephalic trunk was removed, dissected and cut (6 µm). Haematoxylin-eosin staining and modified Van Gieson staining of the cross-sections were performed for computer-assisted analysis of plaque expansion. The plaque composition and the localisation of autophagic and apoptotic proteins in the plaque were examined using immunofluorescent staining and analysed using software.
In agreement with previous studies, GDF-15-/-/ApoE-/--mice showed significantly higher body weight and BMI compared to ApoE-/--mice after 20 weeks of feeding a cholesterol-enriched diet. In addition, consistent with previous studies, a tendency to increase plasma triglyceride levels was observed in GDF-15 deficient ApoE-/--mice. These results suggest that GDF-15 not only influences body mass but also controls lipid balance in the blood. Evaluation of vascular parameters showed a significant reduction in lumen stenosis and lumen area in GDF-15-/-/ApoE-/--mice compared to ApoE-/--mice, confirming GDF-15 as a regulator of atherosclerotic progression. Furthermore, the influence of GDF-15 on the cellular plaque structure in ApoE-/--mice seems to be strongly dependent on the microenvironment in the atherosclerotic lesion according to current scientific knowledge. The results on plaque stability presented here did not show any significance. Based on the simultaneous decrease in luminal stenosis with body weight gain and plasma triglyceride elevation in GDF-15-/-/ApoE-/--mice, we hypothesise that the reduction in atherosclerotic progression by GDF-15 deficiency is apparently not due to the changes in body weight or plasma lipid levels, but that other mechanisms such as autophagy or apoptosis of plaque cells must be involved.
GDF15-/-/ApoE-/--mice showed reduced ATG5+-CD31+-colocalisation area and reduced accumulation of p62 mainly in endothelial cells (CD31+) compared to ApoE-/--mice after 20 weeks of feeding with cholesterol-enriched diet in atherosclerotic plaques. ATG5 is essential for autophagosome formation and p62 accumulation represents autophagosomes in atherosclerotic plaques. Furthermore, increased survivin expression was observed in atherosclerotic plaques in GDF-15-/-/ApoE-/--mice compared to ApoE-/--mice, especially in endothelial cells (CD31+) and in macrophages (CD68+). Interestingly, GDF-15 deficiency also revealed a higher proportion of p53 colocalisation sites with ATG5 in the cytosol of various plaque cells, suggesting a modulation of p53 expression and activation influenced by ATG5. Survivin is a negative apoptosis and autophagy regulator that promotes cell mitosis. p53 is a transcription factor that responds to cellular stress and, upon activation, regulates the expression of cell cycle arrest or proapoptotic proteins. The present study shows that GDF-15 deficiency restricts autophagosome formation and increases survivin expression as an apoptosis and autophagy inhibitor in atherosclerotic plaques, indicating for the first time that GDF-15 is a negative regulator of survivin expression in atherosclerotic plaques. Thus, we hypothesise that the reduced progression, that is the reduced luminal stenosis of atherosclerotic lesion in GDF-15-/-/ApoE-/--mice compared to ApoE-/--mice, is caused by the reduction of ATG5 protein, the decreased p62 accumulation and the increased survivin expression in combination with an apparently efficient efferocytosis.
This work underpins the crucial role of GDF-15 as a regulator of apoptosis and autophagy in atherogenesis. These findings could be useful for the development of new therapeutic approaches in the treatment of atherogenesis.
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Dates
Created: 2025Issued: 2025-10-21Updated: 2025-10-21
Faculty
Medizin
Language
ger
Data types
DoctoralThesis
DFG-subjects
Atherosklersoe, Autophagie, ApoptoseWachstums-Differenzierungs-Faktors-15 (GDF-15)
DDC-Numbers
610
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Heduschke, Aline (Doktor): Rolle des Wachstums-Differenzierungs-Faktors-15 (GDF-15) bei der Regulation von Autophagie bzw. Apoptose und möglicher Einfluss auf die Plaquegröße bei cholesterinreich gefütterten ApoE-/--Mäusen. : Philipps-Universität Marburg 2025-10-21. DOI: https://doi.org/10.17192/z2025.0547.
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