Copyright © 2006, European Society of Cardiology
Intracellular peptides of natriuretic peptide receptor-C inhibit vascular hypertrophy via Gq
/MAP kinase signaling pathways
Department of Physiology, and Groupe de recherche sur le système nerveux autonome, (GRSNA) Faculty of Medicine, University of Montreal, Canada
* Corresponding author. Department of Physiology, Faculty of Medicine, University of Montreal, C. P. 6128, Succ. Centre-ville, Montreal, Quebec, Canada H3C 3J7. Tel.: +1 514 343 2091; fax: +1 514 343 2111. Email address: madhu.anand-srivastava{at}umontreal.ca
Objective: The present studies were undertaken to investigate if the activation of natriuretic peptide receptor-C (NPR-C) that has been shown to inhibit cell proliferation could also modulate the hypertrophic responses of vasoactive peptides in A10 vascular smooth muscle cells (VSMC).
Methods: For these studies A10 VSMC were incubated in the presence of angiotensin II (AngII), endothelin (ET-1) or arginine vasopressin (AVP) alone or in combination with C-ANP4–23 or NPR-C peptides for 24 h and were used for Western blotting and [3H]leucine incorporation. The different peptide fragments used were K461KYRITIERRNH472 (peptide-1) and H481RELREDSIRSH492 (peptide-3) with complete Gi activator sequences and R469RNHQEESNIGK480 (peptide-2) and I465TIERRNH472 (peptideY) with partial Gi activator sequences. The other peptide used had no structural specificity, (Q473EESNIGK480; peptide X) or was the scrambled peptide control for peptide-1 (ITIYKKRRNHRE; peptide Z).
Results: AngII, ET-1 and AVP significantly stimulated protein synthesis in these cells as determined by 3H-leucine incorporation, which was inhibited by peptides 1, 2 and 3 and not by peptides X, Y or Z in a concentration-dependent manner with an apparent Ki between 1–10 nM. In addition, C-ANP4–23 also inhibited protein synthesis stimulated by AngII, ET-1 and AVP; whereas basal protein synthesis in these cells was not inhibited by C-ANP4–23 or by the peptide fragments. Furthermore, AngII-, AVP- and ET-1-induced stimulation of protein synthesis was inhibited by PD98059 (MEK inhibitor) and wortmannin (P13K inhibitor) and this inhibition was potentiated by peptide-1. In addition, peptide-1 was also able to inhibit vasoactive peptide-induced phosphorylation of ERK1/2 and AKT and enhanced the expression of Gq
protein in these cells.
Conclusions: These data suggest that C-ANP4–23 and small peptide fragments containing 12 amino acids from different regions of cytoplasmic domain of NPR-C could modulate vasoactive peptide-stimulated protein synthesis through Gq/MAP kinase/P13K and AKT pathways.
KEYWORDS NPR-C; Peptide-1; Vasoactive peptides; Protein synthesis; ERK1/2; Gq; VSMC
Abbreviations: C-ANP4–23, [des(Glu18, Ser19, Glu20, Leu21, Gly22)ANP4–23-NH2] • AngII, angiotensin II • AVP, arginine vasopressin • ET-1, endothelin • MAPK, mitogen-activated protein kinase • PI3K, phosphatidylinositol 3-kinase • AKT, protein kinase B • VSMC, vascular smooth muscle cells
This study was supported by a grant from the Canadian Institutes of Health Research (MOP 13661).
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