Sirtuin 6 Expression and Inflammatory Activity in Diabetic Atherosclerotic Plaques: Effects of Incretin Treatment

Author:

Balestrieri Maria Luisa1,Rizzo Maria Rosaria2,Barbieri Michelangela2,Paolisso Pasquale2,D’Onofrio Nunzia1,Giovane Alfonso1,Siniscalchi Mario3,Minicucci Fabio3,Sardu Celestino2,D’Andrea Davide3,Mauro Ciro3,Ferraraccio Franca4,Servillo Luigi1,Chirico Fabio5,Caiazzo Pasquale5,Paolisso Giuseppe2,Marfella Raffaele2

Affiliation:

1. Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy

2. Department of Medical, Surgical, Neurological, Aging and Metabolic Sciences, Second University of Naples, Naples, Italy

3. Department of Cardiology, Cardarelli Hospital, Naples, Italy

4. Department of Clinical, Public and Preventive Medicine, Second University of Naples, Naples, Italy

5. Department of Neurosurgery, Cardarelli Hospital, Naples, Italy

Abstract

The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic patients is unknown. We evaluated SIRT6 expression and the effect of incretin-based therapies in carotid plaques of asymptomatic diabetic and nondiabetic patients. Plaques were obtained from 52 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Twenty-two diabetic patients were treated with drugs that work on the incretin system, GLP-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors for 26 ± 8 months before undergoing the endarterectomy. Compared with nondiabetic plaques, diabetic plaques had more inflammation and oxidative stress, along with a lesser SIRT6 expression and collagen content. Compared with non-GLP-1 therapy–treated plaques, GLP-1 therapy–treated plaques presented greater SIRT6 expression and collagen content, and less inflammation and oxidative stress, indicating a more stable plaque phenotype. These results were supported by in vitro observations on endothelial progenitor cells (EPCs) and endothelial cells (ECs). Indeed, both EPCs and ECs treated with high glucose (25 mmol/L) in the presence of GLP-1 (100 nmol/L liraglutide) presented a greater SIRT6 and lower nuclear factor-κB expression compared with cells treated only with high glucose. These findings establish the involvement of SIRT6 in the inflammatory pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin, the effect of which is associated with morphological and compositional characteristics of a potential stable plaque phenotype.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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