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

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 6 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-kB 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.Cardiovascular disease represents the leading cause of death in patients with type 2 diabetes (1). Diabetes leads to increased vulnerability for plaque disruption, and mediates increased incidence and severity of clinical events (2). Inflammation, particularly in diabetes, plays a central role in the cascade of events that result in plaque erosion and fissuring (2). There is now increasing evidence that a number of transcription factors, including the Sir2 family of enzymes, namely sirtuins (SIRTs), regulate multiple genes whose products are putatively involved in the regulation of inflammation and endothelial cell (EC) function (3). The Sir2 family consists of seven enzymes (SIRT1 to SIRT7) that share a conserved core catalytic domain, but differ in their cellular localization and tissue distribution (4). Among the SIRTs, SIRT6, a chromatinassociated deacetylase, is considered to have a leading role in regulating genomic stability, cellular metabolism, stress response, and aging (5-8). A recent study (9) in mice suggested a role for SIRT6 in inflammation. Moreover, the knockdown of SIRT6 resulted in the increased expression of proinflammatory cytokines (interleukin [IL]-1b, IL-6, and IL-8), extracellular matrix remodeling enzymes (matrix metalloproteinase [MMP]-2, MMP-9, and plasminogen activator inhibitor 1), and intracellular adhesion molecule-1 (4). In ECs, the loss of SIRT6 was associated with an increased expression of nuclear factor-kB (NF-kB), whereas o...

Sitagliptin Attenuates the Progression of Carotid Intima-Media Thickening in Insulin-Treated Patients With Type 2 Diabetes: The Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE)

“…In addition, a subanalysis of the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) demonstrated that the relationships between serum biomarkers of chronic inflammation and endothelial injury at multiple time points and the progression of carotid IMT remain unclear in patients with type 1 diabetes (29). Interestingly, a recent report suggested that evaluation of local inflammation and oxidative stress in the vascular wall, not in serum, was helpful in the full assessment of "non-glycaemicdependent" antiatherosclerotic effects of DPP-4 inhibitors (30).…”

“…#P , 0.01. §P , 0.001. subjects of the above-mentioned three trials (29)(30)(31) were patients with T2DM with a history of CVD or at high risk for CVD. In comparison, our study enrolled insulin-treated subjects with T2DM who were free from apparent CVD.…”

Sirtuin-6 Preserves R-spondin-1 Expression and increases Resistance of intestinal Epithelium to injury in Mice

“…Sirt6 protein expression is downregulated in diabetic atherosclerotic lesions (38). A previous study identified that H 2 O 2 treatment results in marked reduction of Sirt6 in endothelial cells (39).…”

GLP-1 receptor agonists, carotid atherosclerosis and retinopathy

“…On the other hand, the effect of incretin-based therapies on carotid plaques should be mentioned. The findings indicate on beneficial effects of GLP-1RA on morphological and compositional characteristics of a plaque phenotype through the sirtuin 6 pathway [7]. Further investigations will elucidate this relationship and show if such effects may translate into a reduction of CV events in T2DM subjects.…”