Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes - Archive ouverte HAL Access content directly
Journal Articles Communications Biology Year : 2018

Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes

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Khurrum Shahzad
  • Function : Author
Ihsan Gadi
  • Function : Author
Sumra Nazir
  • Function : Author
Moh’d Mohanad Al-Dabet
  • Function : Author
Shrey Kohli
  • Function : Author
Fabian Bock
  • Function : Author
Lukas Breitenstein
  • Function : Author
Satish Ranjan
  • Function : Author
Tina Fuchs
  • Function : Author
Zuhir Halloul
  • Function : Author
Peter P Nawroth
  • Function : Author
Pier Giuseppe Pelicci
  • Function : Author
Ruediger C Braun-Dullaeus
  • Function : Author
Eric Camerer
Charles T Esmon
  • Function : Author
Berend Isermann
  • Function : Author

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 pro-atherogenic phenotype are sustained despite restoring normoglycemic conditions. Inhibition of p66Shc abolishes this sustained pro-atherogenic 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.

Dates and versions

hal-03906182 , version 1 (19-12-2022)

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Cite

Khurrum Shahzad, Ihsan Gadi, Sumra Nazir, Moh’d Mohanad Al-Dabet, Shrey Kohli, et al.. Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes. Communications Biology, 2018, 1 (1), pp.104. ⟨10.1038/s42003-018-0108-5⟩. ⟨hal-03906182⟩
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