VASCULOPROTECTIVE ROLE OF NATRIURETIC PEPTIDE RECEPTOR C
Madhu B. Anand-Srivastava, Ph.D., University of Montreal, Montreal, Quebec, Canada
VSMC from spontaneously hypertensive rats (SHR) exhibit enhanced proliferation and hypertrophy. We earlier showed that small peptide fragments of cytoplasmic domain of natriuretic receptor-C (NPR-C) attenuate vasoactive peptide-induced hyperproliferation and hypertrophy of VSMC, the key players of vascular remodeling. We undertook the studies to investigate if a specific agonist of NPR-C, C-ANP4-23, could attenuate the VSMC hypertrophy, hyperproliferation as well as hypertension in SHR, and examine the underlying signaling pathways contributing to this inhibition. C-ANP4-23 treatment of SHR attenuated the development of hypertension as well as hyperproliferation of aortic VSMC to control levels. In addition, C-ANP4-23 restored the overexpression of cyclin D1, cyclin A, cyclin E, cyclin dependent kinase 2/4, phosphorylated retinoblastoma protein, Gialpha proteins, peroxynitrite and the decreased expression of p21Cip1 and p27Kip1 exhibited by VSMC from SHR. C-ANP4-23 treatment of VSMC from SHR also attenuated the enhanced protein synthesis (hypertrophy) as well as the enhanced expression of Gqalpha and PLCbeta1 proteins implicated in hypertrophy. Furthermore, the enhanced phosphorylation of ERK1/2, AKT, EGF-R, PDGF-R, IGF-R and c-Src, enhanced levels of superoxide anion, NADPH oxidase activity, and enhanced expression of Nox1, Nox2, Nox4 and P47phox in SHR were all attenuated by C-ANP4–23 treatment. These results indicate that NPR-C activation by C-ANP4-23 attenuates VSMC hypertrophy, hyperproliferation and hypertension. and suggest that NPR-C has a vasculoprotective role and that NPR-C ligand C-ANP4-23 may have the potential to be used as therapeutic agent in the treatment of cardiovascular complications including hypertension and atherosclerosis.
(Supported by grant from Heart and Stroke Foundation of Canada).