The DPP-4 inhibitor sitagliptin attenuates the progress of atherosclerosis in apolipoprotein-E-knockout mice via AMPK- and MAPK-dependent mechanisms

Abstract

BackgroundThe dipeptidyl peptidase-4 inhibitor sitagliptin, a new anti-diabetic medicine, is effective in treating type 2 diabetes mellitus by increasing the activation and duration of action of glucagon-like peptide-1. Since atherosclerosis is the main pathological feature of diabetic cardiovascular complications, it is important to investigate the anti-atherosclerotic effect of sitagliptin and explore the relevant mechanisms.MethodsMale apolipoprotein-E-knockout mice were randomly divided into two groups and fed either high-fat diet (HFD) or HFD plus sitagliptin at a concentration of 0.3% for 16 weeks. Body weight, food intake, blood glucose, serum lipids and adhesion molecules were measured. The atherosclerotic plaque area and its histological composition were analyzed using Sudan staining and immunohistochemistry. The expression of inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6) and the activation of AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) in the aortas were determined using quantitative polymerase chain reaction and western blot, respectively.ResultsMice treated with sitagliptin developed fewer atherosclerotic plaques than the control group (7.64 ± 1.98% vs 12.91 ± 1.15%, p < 0.001), particularly in the aortic arch and abdominal aorta, where plaques were decreased 1.92- and 2.74-fold, respectively (p < 0.05 and p < 0.01). Sitagliptin significantly reduced the content of collagen fiber in plaques 1.2-fold (p < 0.05). Moreover, sitagliptin significantly reduced the expression of monocyte chemoattractant protein-1 and interleukin-6 in the aorta (p < 0.01 and p < 0.05), as well as the serum levels of soluble vascular cell adhesion molecule-1 and P-selectin (both p < 0.05). In addition, Sitagliptin induced phosphorylation of AMPK and Akt (p < 0.05 and p < 0.01), while suppressed phosphorylation of p38 and extracellular signal-regulated kinase (Erk) 1/2 (p < 0.05 and p < 0.01) in aortas.ConclusionsOur present study indicates that sitagliptin can reduce the area of the atherosclerotic lesion, possibly by regulating the AMPK and MAPK pathways and then reducing leukocyte –endothelial cell interaction and inflammation reactions. These actions are independent of weight loss and glucose-reducing effects.

Sitagliptin attenuates inflammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition

“…These inflammatory cytokines were reduced in the presence of sitagliptin, suggesting that sitagliptin has inhibitory effects on inflammation in response to proinflammatory agents such as LPS, which can lead to cardiovascular depression during sepsis. The present results are consistent with previous studies which have shown that sitagliptin can lead to reduced levels of proinflammatory markers, and may potentially contribute to the inhibition of cardiovascular complications (29,30).…”

Interleukin-4 regulates macrophage polarization via the MAPK signaling pathway to protect against atherosclerosis

“…In addition, leukocyte cell-derived chemotaxin 2 (LECT2) can also play a role in atherosclerotic inflammatory reactions via JNK phosphorylation (Hwang et al, 2015). In addition, the DPP-4 inhibitor sitagliptin can reduce leukocyte-endothelial cell interactions and inflammation, and attenuate atherosclerosis progression via AMPK-and MAPK-dependent mechanisms (Zeng et al, 2014). Haeng Park et al (2014) also confirmed that the anti-atherosclerotic effects of Polygonum aviculare L. ethanol extract in ApoE -/-mice are mediated via the MAPK pathway.…”

Effect of L-Carnitine and/or Sitagliptin on Serum Lipids Profile of H2O2 Treated Rats (Part-1)

“…Besides, DPP-4 inhibitors has been found to reduce hepatic expression of genes important for cholesterol synthesis (Flock et al, 2013). Sitagliptin reduced atherosclerosis progression in hyperlipidemic rabbits via its effect on lipid parameters and interfering with inflammatory and oxidative stress pathway (Zeng et al, 2014). However molecular and cellular mechanisms of how this drug lower lipid level (e.g.…”