Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice

Abstract

Diabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.

Inflammation and Oxidative Stress Role of S100A12 as a Potential Diagnostic and Therapeutic Biomarker in Acute Myocardial Infarction

“…In addition, S100A12 was identified to be involved in the development of atherosclerosis through the S100A12-CD36 axis, and its expression was upregulated in unstable plaques [ 23 ]. It was also previously reported that tumor necrosis factor alpha (TNF- α )+S100A12 treatment stimulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and the production of hydrogen peroxide (H2O2) in human aortic smooth muscle cells (HASMCs) [ 24 ]. The above evidence suggests that S100A12 plays an essential part in inflammation and oxidative stress in numerous diseases.…”

Therapeutic Perspectives of CD26 Inhibitors in Imune-Mediated Diseases

“…Saxagliptin reduced CD40 expression in inflammatory monocytes and macrophages implicated in the initiation of atherosclerosis [ 11 ]. Sitagliptin is also reported to decrease vascular calcification [ 37 ]. Lin et al reported that sitagliptin also prevents the initiation of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, which is followed by a decrease in receptors for advanced glycation end products (RAGE) expression [ 37 ].…”

“…Sitagliptin is also reported to decrease vascular calcification [ 37 ]. Lin et al reported that sitagliptin also prevents the initiation of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, which is followed by a decrease in receptors for advanced glycation end products (RAGE) expression [ 37 ]. There is evidence suggesting sitagliptin stimulates the adenosine monophosphate-activated protein kinase (AMPK) pathway and inhibits the mitogen-activated protein kinase (MAPK) pathway, both of which are implicated in inflammation and atherosclerosis [ 12 ].…”

Contribution of Oxidative Stress (OS) in Calcific Aortic Valve Disease (CAVD): From Pathophysiology to Therapeutic Targets

“…These included treatment with NO donors application (DETA-NONOate) [ 184 ], sodium nitroprusside (SNP) [ 185 ], NO precursor L-arginine [ 186 ], and co-treatment with BH4, which mitigates eNOS uncoupling, showing modest results in attenuating osteogenic differentiation and endothelial dysfunction [ 15 , 187 , 188 ]. Consecrated therapies, such as angiotensin-converting enzyme (ACE) inhibitors [ 96 ], nebivolol [ 45 ], inhibitors of dipeptidyl peptidase 4 (DPP4), such as sitagliptin and anagliptin [ 89 , 122 , 189 , 190 ], and empagliflozin, a sodium–glucose cotransporter-2 (SGLT2) inhibitor [ 25 ], also interfere and prevent eNOS uncoupling and suppress superoxide production. Currently, there are no RCTs testing the aforementioned theories, lending credence that NO bioavailability modulators might be a cutting-edge therapy in CAVD in the future.…”