Abstract 17049: Depeptidyl Peptidase-4 Has A Crucial Role In Pulmonary Arterial Smooth Muscle Cell (PASMC) Proliferation Through Interaction Between Activated T Cells And PASMCs
Background: Inflammation is very important for pathophysiology of Pulmonary arterial hypertension (PAH). Dipeptidyl peptidase-4 (DPP-4) plays a crucial role for degrading the incretin hormones that regulates insulin secretion. It is also known that DPP-4 has an important role as a co-stimulatory function for T cell activation. In our present study, we investigated the role of DPP-4 in PAH.
Methods: 40 Sprague Dawley rats were given a single cutaneous injection of monocrotaline (MCT). Starting at day 14 after MCT injection, we administered daily a DPP-4 inhibitor alogliptin (M + A group) or vehicle (M group). We examined in in vivo and in vitro as follows.
Results: In in vitro experiments, 45% of (M + A) group were still alive at day 30 compared to 5% of M group. Alogliptin markedly improved the right ventricular pressure (33 ± 4.1 mmHg in (M + A) group vs 85.9 ± 1.2 mmHg in M group) in cardiac catheterization. Fibroblast growth factor 2 (FGF2) mRNA level decreased in (M + A) group compared to M group. In in vitro experiments, alogliptin suppressed pulmonary arterial smooth muscle cell (PASMC) nuclear factor kappa B (NF-kB) p65 translocation into the nucleus in western blot analysis. In lung tissues, CTLA-4 (cytotoxic T lymphocyte antigen 4), LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry mediator on T lymphocytes), and CD86 (cluster of Differentiation 86) mRNA levels, all of which were T-cell co-stimulatory molecules, decreased in (M + A) group compared to M group. Immunohistochemistry revealed that the number of CTLA-4 positive T cells attenuated in (M + A) group than in M group. In addition, alogliptin suppressed phosphorylations both extracellular regulated kinase1/2 and phopholipase C, both of which were regulated by CD86, in PASMCs stimulated with FGF2.
Conclusion: Those results suggest that DPP-4 has a crucial role in PASMC proliferation through interaction between activated T cells and PASMCs. DPP-4 inhibitor alogliptin has potential as a new therapeutic tool for PAH.
- © 2013 by American Heart Association, Inc.