Abstract 480: Increased Expression of Dipeptidyl Peptidase-4 in Atherosclerosis: A Role for TLR4/MyD88 Signaling

Abstract

OBJECTIVE: Dipeptidyl peptidase-4 (DPP4) is a ubiquitously expressed peptidase with high levels of expression on innate and adaptive cell populations. DPP4 expression is upregulated in a number of conditions associated with inflammatory activation of macrophages. In this study we attempted to understand the mechanisms by which DPP4 is regulated in atherosclerosis. METHODS AND RESULTS: We compared DPP4 expression on patients with stable established cardiovascular disease (SCVD, n=20) and compared them with control subjects without atherosclerosis using flow cytometry. Compared to healthy controls, SCVD patients had increased DPP4 expression on peripheral monocytes (4.22 ± 0.44 vs. 5.76 ± 0.44, in control vs. SCVD, p=0.037) and T cells (27.46 ± 2.67 vs. 48.06 ± 1.96, control vs. SCVD, p<0.0001). DPP4 expression on T cells and monocytes correlated with plasma non-HDL level (R 2 =0.153, p=0.036 and R 2 =0.244, 0.012 respectively). In cultured peripheral blood mononuclear cells (PBMCs) stimulated with LPS, DPP4 expression increased 4-fold compared to control cells. Increased DPP4 with LPS was abrogated by Toll-like receptor 4 (TLR4)-specific siRNA knockdown. Macrophages deficient for MyD88, an adaptor protein for Toll-like receptor signaling, displayed reduced expression of DPP4. Consistent with that, MyD88 -/- mice demonstrating improved post-prandial glycemia to oral glucose challenge. CONCLUSIONS: DPP4 expression is up-regulated in atherosclerosis and involves TLR4-MyD88 dependent activation. Our result suggest a role for this pathway in metabolic dysregulation and inflammation in atherosclerosis.