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.
Highlights
Impaired activated protein C generation is associated with atherosclerosis and diabetes mellitus
We previously reported that activated protein C (aPC) normalizes glucose-induced p66Shc expression in podocytes[16], suggesting that impaired aPC generation in the context of diabetes mellitus may contribute to sustained p66Shc expression and to the hyperglycaemic memory in diabetic patients
While impaired thrombomodulin-dependent protein C activation has been mechanistically linked with diabetic microangiopathy[1,16,22,23], the role of aPC in diabetic macroangiopathy remained unknown
Summary
Impaired activated protein C (aPC) generation is associated with atherosclerosis and diabetes mellitus. Epigenetically sustained p66Shc expression in plaque macrophages drives the hyperglycaemic memory, which ——can be reversed by aPC. This establishes that reversal of the hyperglycaemic memory in diabetic atherosclerosis is feasible. Expression of p66Shc is epigenetically controlled, suggesting that sustained p66Shc expression may provide a mechanistic link between the hyperglycaemic memory, sustained vascular ROS generation and inflammation, and progressive atherosclerotic disease despite improved blood glucose control[16,19]. We demonstrate that aPC reverses the glucoseinduced, epigenetically sustained p66Shc expression in atherosclerotic plaque-associated macrophages, promoting the reversal of hyperglycaemia-induced atherosclerotic plaques
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