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Title: Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes mellitus
Author(s): Gadi, Ihsan-Ur-Rehman Khan
Referee(s): Dudeck, Anne
Chavakis, Triantafyllos
Granting Institution: Otto-von-Guericke-Universität Magdeburg
Issue Date: 2021
Type: Doctoral thesis
Language: English
Publisher: Otto-von-Guericke-Universität Magdeburg
URN: urn:nbn:de:gbv:ma9:1-1981185920-879509
Subjects: Arteriosklerose
Diabetes mellitus
Oxidativer Stress
Abstract: 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.
Open Access: Open access publication
License: (CC BY-SA 4.0) Creative Commons Attribution ShareAlike 4.0(CC BY-SA 4.0) Creative Commons Attribution ShareAlike 4.0
Appears in Collections:Medizinische Fakultät

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