Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Attenuates Arterial Calcification By Downregulating Oxidative Stress-Induced Receptor for Advanced Glycation End Products in Low-Density Lipoprotein Receptor Knockout Mice

Abstract

Background: Plasma advanced glycation end products (AGEs) activates the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus patient vascular complications. Attenuating the activation of RAGE may exert a protective effect against the development of cardiovascular disease. Dipeptidyl peptidase-4 (DPP4) inhibitors are a new class of oral hypoglycemic agents for the treatment of type 2 diabetes mellitus. Whether sitagliptin, a DPP-4 inhibitor, has a beneficial effect on vascular calcification remains undetermined. Methods: In the present study, we fed low-density lipoprotein receptor knockout (LDLR-/-) mice a high fat diet to induce diabetic mellitus and studied the effect of orally administered sitagliptin on the high fat diet fed LDLR-/- mice aorta medial calcification, RAGE expression, oxidative stress, aorta calcium content. Tumor necrosis factor (TNF)-α combined with S100A12 was used to induce HASMC oxidative stress, activation of NADPH, up-regulation of the bone markers and RAGE expression, and cell calcium deposition. Effect of sitagliptin, siRNA for RAGE and apocynin on blunting TNF-α and S100A12 induced HASMC oxidative stress, calcification and NADPH activation were also investigated. Results: Sitagliptin attenuated the HFD-induced LDLR-/- mice hyperlipidemia, hyperglycemia, increase in serum TNF-α, aorta calcium deposition and the expression of RAGE in the medial layer of the aorta. TNF-α combined with S100A12 stimulated HASMC RAGE expression, calcium deposition, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activation, and up-regulation of bone marker (bone morphogenetic protein-2, Msh homeobox 2, and runt‑related transcription factor 2) expression. Sitagliptin and apocynin (APO), an NADPH oxidase inhibitor, suppressed the TNF-α+S100A12 treatment effects on the activation of NADPH oxidase and Nuclear factor (NF)-κB and the resultant oxidative stress, up-regulation of RAGE and bone markers expression and calcium deposition. Our findings suggest that sitagliptin imparts its protective effect by suppressing NADPH oxidase and NF-κB activation to blunt the up-regulation of RAGE expression.Conclusion: Our findings suggest that sitagliptin may suppress the initiation and progression of artery calcification by inhibiting the activation of NADPH oxidase and NF-κB and the resultant up-regulation of expression of RAGE.

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

“…Alternative therapies that inhibit LDL oxidation and that are not yet proven to be directly correlated to CAVD may be represented by probucol [ 24 ], sitagliptin, and alogliptin [ 34 , 122 ]. Moreover, aegeline, a compound anti-lectin-like oxidized-LDL receptor-1 (LOX-1) [ 77 ], as well as capsaicin [ 123 ], kefir peptides [ 73 ], and p38 MAPK inhibitors dilmapimod (SB681323, GlaxoSmithKline, London, UK) and losmapimod (GW856553, GlaxoSmithKline, London, UK) [ 55 ], are currently under investigation.…”

“…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.…”

“…Antidiabetic therapies, such as sitagliptin, showed pleiotropic effects in NOX by additionally inhibiting the cross-talk between RAGE/NF-κB with implications in calcific remodeling [ 21 , 89 , 122 ]. By reducing TNF-α, Il-6, iNOS, and NOX2 expression, the GLP-1 analog liraglutide also reduced vascular dysfunction, aortic inflammation, and oxidative stress in mice with polymicrobial sepsis [ 192 ].…”