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Small cytoplasmic domain peptides of natriuretic peptide receptor-C attenuate cell proliferation through G_i protein/MAP kinase/PI3-kinase/AKT pathways

Department of Physiology and Groupe de recherche sur le système nerveux autonome, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

Submitted 29 March 2006 ; accepted in final form 10 August 2006

The present studies were undertaken to investigate the effect of C-atrial natriuretic peptide (ANP)_4–23 and several peptide fragments containing 12 amino acids from different regions of the cytoplasmic domain of natriuretic peptide receptor (NPR)-C on cell proliferation in the absence or presence of angiotensin (ANG) II, endothelin (ET)-1, and arginine vasopressin (AVP) in A-10 vascular smooth muscle cells (VSMC). The peptide fragments used have either complete G_i activator sequences K⁴⁶¹-H⁴⁷² (peptide 1) and H⁴⁸¹-H⁴⁹² (peptide 3) or partial G_i activator sequences R⁴⁶⁹-K⁴⁸⁰ (peptide 2) and I⁴⁶⁵-H⁴⁷² (peptide Y) with truncated COOH or NH₂ terminus, respectively. The other peptide used had no structural specificity (Q⁴⁷³-K⁴⁸⁰, peptide X) or was the scrambled peptide control for peptide 1 (peptide Z). ANG II, ET-1 and AVP significantly stimulated DNA synthesis in these cells as determined by [³H]thymidine incorporation that was inhibited by peptides 1, 2, and 3 and not by peptides X, Y, and Z in a concentration-dependent manner, with an apparent K_i between 1 and 10 nM. In addition, C-ANP_4–23, which interacts with NPR-C, also inhibited DNA synthesis stimulated by vasoactive peptides; however, the inhibition elicited by C-ANP_4–23 was not additive with the inhibition elicited by peptide 1. On the other hand, basal DNA synthesis in these cells was not inhibited by C-ANP_4–23 or the peptide fragments. Furthermore, vasoactive peptide-induced stimulation of DNA synthesis was inhibited by PD-98059 and wortmannin, and this inhibition was potentiated by peptide 1. In addition, peptide 1 also inhibited vasoactive peptide-induced phosphorylation of ERK1/2 and AKT and enhanced expression of G_i proteins. These data suggest that C-ANP_4–23 and small peptide fragments containing 12 amino acids irrespective of the region of the cytoplasmic domain of NPR-C inhibit proliferative responses of vasoactive peptides through G_i protein and MAP kinase/phosphatidylinositol 3-kinase/AKT pathways.

vasoactive peptides; DNA synthesis; extracellular signal-regulated kinase 1/2; peptide 1; vascular smooth muscle cell

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