Abstract 503: Dipeptidyl Peptidase-4 Regulates Proliferation of and Collagen Synthesis by Cardiac Fibroblasts
Dipeptidyl peptidase-4 (DPP4) inhibitors, for example sitagliptin, are a new class of drugs for treatment of type 2 diabetes. Because there are multiple peptide substrates for DPP4, inhibition of DPP4 may entail risks due to augmented levels of biologically active peptides. The purpose of this study was to investigate the role of DPP4 in regulating the effects of two of its substrates, neuropeptide Y1-36 (NPY1-36) and peptide YY1-36 (PYY1-36) (naturally occurring Y1 receptor agonists) on proliferation of and collagen production by cardiac fibroblasts (CFs) from spontaneously hypertensive (SHR) and Wistar-Kyoto normotensive (WKY) rats. For proliferation experiments, subconfluent cells were treated every 24 hours for 4 days with platelet-derived growth factor-BB (PDGF) and various treatments, and cells were dislodged and counted. For collagen synthesis experiments, confluent cells were treated with PDGF, tritiated-L-proline and various treatments, and after 48 hours radioactivity in cells was quantified. In both SHR and WKY CFs, both NPY1-36 and PYY1-36 (1 to 10 nmol/L) increased cell number and proline incorporation (index of collagen synthesis). Sitagliptin (1 μmol/L) significantly enhanced these effects. For example, in SHR CFs 10 nmol/L of NPY1-36 increased cell number from 37,588 ± 503 to 51,990 ± 649; yet in the presence of sitagliptin, NPY1-36 increased cell number from 37,964 ± 508 to 62,047 ± 939 (mean ± SEM, n=6; p<0.000001, p-value for interaction between sitagliptin and NPY1-36). In both SHR and WKY CFs and in both the absence and presence of sitagliptin, BIBP3226 (1 μmol/L; Y1 receptor antagonist) blocked all effects of NPY1-36 and PYY1-36. Because DPP4 metabolizes NPY1-36 to NPY3-36 and PYY1-36 to PYY3-36, we also determined the effects of NPY3-36 and PYY3-36 on proliferation and collagen production. In both SHR and WKY CFs, these metabolites did not affect proliferation or collagen production, either in the absence or presence of sitagliptin.
Conclusion: In cultured CFs, DPP4 inhibitors increase NPY1-36 and PYY1-36 induced activation of Y1 receptors leading to increased proliferation and collagen production. Therefore, DPP4 inhibitors might increase cardiac fibrosis in patients with chronically elevated levels of NPY1-36 or PYY1-36.
- © 2013 by American Heart Association, Inc.