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Titel: Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes mellitus
Autor(en): Gadi, Ihsan-Ur-Rehman Khan
Gutachter: Dudeck, Anne
Chavakis, Triantafyllos
Körperschaft: Otto-von-Guericke-Universität Magdeburg
Erscheinungsdatum: 2021
Art: Dissertation
Sprache: Englisch
Herausgeber: Otto-von-Guericke-Universität Magdeburg
URN: urn:nbn:de:gbv:ma9:1-1981185920-879509
Schlagwörter: Arteriosklerose
Diabetes mellitus
Oxidativer Stress
Zusammenfassung: Impaired activated protein C (aPC) generation is associated with atherosclerosis and diabetes mellitus. Diabetes-associated atherosclerosis is characterized by the hyperglycaemic memory, e.g. failure of disease improvement despite attenuation of hyperglycaemia. Therapies reversing the hyperglycaemic memory are lacking. Here we demonstrate that hyperglycaemia, but not hyperlipidaemia, induces the redox-regulator p66Shc and reactive oxygen species (ROS) in macrophages. p66Shc expression, ROS generation, and a proatherogenic phenotype are sustained despite restoring normoglycemic conditions. Inhibition of p66Shc abolishes this sustained proatherogenic phenotype, identifying p66Shc-dependent ROS in macrophages as a key mechanism conveying the hyperglycaemic memory. The p66Shc-associated hyperglycaemic memory can be reversed by aPC via protease-activated receptor-1 signalling. aPC reverses glucose-induced CpG hypomethylation within the p66Shc promoter by induction of the DNA methyltransferase-1 (DNMT1). Thus, epigenetically sustained p66Shc expression in plaque-macrophages drives the hyperglycaemic memory, which – however – can be reversed by aPC. This establishes that reversal of the hyperglycaemic memory in diabetic atherosclerosis is feasible.
URI: https://opendata.uni-halle.de//handle/1981185920/87950
http://dx.doi.org/10.25673/85997
Open-Access: Open-Access-Publikation
Nutzungslizenz: (CC BY-SA 4.0) Creative Commons Namensnennung - Weitergabe unter gleichen Bedingungen 4.0 International(CC BY-SA 4.0) Creative Commons Namensnennung - Weitergabe unter gleichen Bedingungen 4.0 International
Enthalten in den Sammlungen:Medizinische Fakultät

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