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

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

doi:10.1038/s42003-018-0108-5

Activated protein C reverses epigenetically sustained p66^Shc expression in plaque-associated macrophages in diabetes

Commun Biol. 2018 Aug 6:1:104. doi: 10.1038/s42003-018-0108-5. eCollection 2018.

Authors

Khurrum Shahzad^{1

2}, Ihsan Gadi³, Sumra Nazir³, Moh'd Mohanad Al-Dabet³, Shrey Kohli³, Fabian Bock^{3

4}, Lukas Breitenstein³, Satish Ranjan³, Tina Fuchs⁵, Zuhir Halloul⁶, Peter P Nawroth⁷, Pier Giuseppe Pelicci⁸, Ruediger C Braun-Dullaeus⁹, Eric Camerer¹⁰, Charles T Esmon¹¹, Berend Isermann¹²

Affiliations

¹ Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Leipziger Straße 44, 39120, Magdeburg, Germany. khurrum.shahzad@med.ovgu.de.
² Department of Biotechnology, University of Sargodha, Sargodha, 40100, Pakistan. khurrum.shahzad@med.ovgu.de.
³ Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Leipziger Straße 44, 39120, Magdeburg, Germany.
⁴ Department of Medicine, Vanderbilt University Medical Center, 37232, Nashville, TN, USA.
⁵ Institute for Clinical Chemistry, University of Heidelberg Medical Faculty Mannheim, 68167, Mannheim, Germany.
⁶ Division of Vascular Surgery, Department of General, Abdominal and Vascular Surgery Otto-von-Guericke-University, Leipziger Straße 44, 39120, Magdeburg, Germany.
⁷ Department of Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, 69120, Heidelberg, Germany.
⁸ Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141, Milan, Italy.
⁹ Department of Internal Medicine, Division of Cardiology and Angiology, Otto-von-Guericke-University, Leipziger Straße 44, 39120, Magdeburg, Germany.
¹⁰ INSERM U970, Paris Cardiovascular Research Centre, 75015, Paris, France.
¹¹ Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, and Department of Pathology and Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, OK, USA.
¹² Institute of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Leipziger Straße 44, 39120, Magdeburg, Germany. berend.isermann@med.ovgu.de.

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 p66^Shc and reactive oxygen species (ROS) in macrophages. p66^Shc expression, ROS generation, and a pro-atherogenic phenotype are sustained despite restoring normoglycemic conditions. Inhibition of p66^Shc abolishes this sustained pro-atherogenic phenotype, identifying p66^Shc-dependent ROS in macrophages as a key mechanism conveying the hyperglycaemic memory. The p66^Shc-associated hyperglycaemic memory can be reversed by aPC via protease-activated receptor-1 signalling. aPC reverses glucose-induced CpG hypomethylation within the p66^Shc promoter by induction of the DNA methyltransferase-1 (DNMT1). Thus, epigenetically sustained p66^Shc 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.

Grants and funding

UM1 HL120877/HL/NHLBI NIH HHS/United States