Dipeptidyl Peptidase 4 Inhibitors Augment the Activation of Cardiac Fibroblasts by SDF-1α, Neuropeptide Y, and Peptide YY

Undergraduate #50
Discipline: Biological Sciences
Subcategory: Cell and Molecular Biology

Jasmine Johnson - University of Arkansas at Pine Bluff
Co-Author(s): Delbert G. Gillespie and Edwin K. Jackson, Molecular Pharmacology, SURP, University of Pittsburgh

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Dipeptidyl Peptidase 4 (DPP4) inhibitors, for example sitagliptin, are a class of antidiabetic drugs that increase insulin release by blocking the metabolism of incretins, which are insulin releasing hormones. Several randomized controlled clinical trials and observational studies suggest that DPP4 inhibitors increase the risk of heart failure, although the mechanism remains unclear. We hypothesize that DPP4 inhibitors, by blocking the metabolism (inactivation) of peptides such as SDF-1α, neuropeptide Y (NPY), and peptide YY (PYY), stimulate the proliferation of and extracellular matrix production by cardiac fibroblasts (CFs), a process that could induce cardiac fibrosis and dysfunction. To test this concept, we examined whether sitagliptin augments the effects of SDF-1α, NPY, and PYY on cell proliferation (by cell counting), total collagen production (by proline incorporation), and collagen I synthesis (by ELISA) in CFs obtained from genetically hypertensive rats. The results showed that both NPY and PYY augment the proliferation of CFs and that this response is enhanced by sitagliptin. Similar results were obtained with SDF-1α. To date these findings support our hypothesis and suggest that antagonists of SDF-1α receptors (CXCR4) or NPY/PYY receptors (Y1) could improve the clinical safety of DPP4 inhibitors.

Funder Acknowledgement(s): LSAMP, American Society for Pharmacology and Experimental Theurapetics

Faculty Advisor: Annissa Buckner, buckner.ae@gmail.com

Role: I did most of the research in this experiment. I set up the experiment and ran the experiment that only part that I was assisted on was running the samples through the certain instrumentation.