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Article Dans Une Revue Communications Biology Année : 2018

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

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

Résumé

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 et versions

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

Identifiants

Citer

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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