Role of dipeptidylpeptidase IV (DPPIV) on growth-promoting effects of neuropeptide Y in vascular smooth muscle cells

Neuropeptide Y, NPY(1-36), is a sympathetic neurotransmitter and endothelium-derived growth factor causing vasoconstriction via Y1 receptors, and endothelial and vascular smooth muscle cell (VSMC) growth via Y1, Y2, and Y5 receptors. With a proline in the penultimate position, NPY(1-36) is substrate for dipeptidylpeptidase IV (DPPIV), which cleaves Tyr(1)-Pro(2) and forms NPY(3-36), which is inactive at Y1 receptors, but active at Y2 and Y5 receptors. Therefore, it was hypothesized that DPPIV is a modulator of NPY-induced mitogenesis, and is expressed or inducible in VSMCs.; Aims included determination of whether DPPIV (1) is expressed (mRNA and protein) and enzymatically active in rat and human VSMCs, (2) has enzymatic activity that modulates NPY-induced mitogenesis, and (3) expression or activity is modulated during in-vitro VSMC injury (starvation) or in-vivo following balloon angioplasty and neointima formation in rat carotid arteries.; Primary and subcultured rat and human aortic VSMCs expressed DPPIV mRNA (semi-quantitative RT-PCR), protein (membrane and cytoplasm immunostaining), and enzymatic activity.; NPY(1-36) evoked mitogenesis in rat and human VSMCs at lower, but not higher, passages; rat VSMCs exhibited earlier and greater up-regulation of NPY-induced DPPIV and Y2/Y5 expression. Tyr(1)-Pro(2) and NPY(3-36) alone mimicked NPY, and synergized NPY's mitogenic effect when combined in parallel to the fragment-induced upregulation of Y2 and Y5 mRNA.; Human DPPIV enzyme (hDDPIV+) and DPPIV-specific Wilk Inhibitor were mitogenic, per se, but the enzyme did not augment, and the inhibitor did not block, NPY-mediated mitogenesis, suggesting actions partially independent, possibly due to divergent effects on Y2, Y5, or DPPIV expression.; In vitro, starvation (induced by serum-deprivation), and NPY, augmented DPPIV enzymatic activity in VSMCs. In vivo, angioplasty up-regulated DPPIV expression and this corresponded to neointima formation; neointima formation was markedly augmented by NPY slow-release pellets placed next to the injured artery.; Thus, DPPIV is expressed in VSMCs, stimulates proliferation, and it modulates NPY's actions by altering receptor expression. Due to the mitogenic activity of the inhibitor, and existence of other exopeptidases in VSMCs, these studies suggest and support, but do not prove, the role of DPPIV in vascular remodeling, in general, and specifically in response to NPY.