Abstract
Vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit hyperproliferation and overexpression of cell cycle proteins. We earlier showed that small peptide fragments of cytoplasmic domain of natriuretic receptor-C (NPR-C) attenuate vasoactive peptide-induced hyperproliferation of VSMC. The present study investigated if C-ANP4–23, a specific agonist of NPR-C, could attanuate the hyperproliferation of VSMC from SHR by inhibiting the overexpression of cell cycle proteins and examine the underlying signaling pathways contributing to this inhibition. The proliferation of VSMC was determined by [3H] thymidine incorporation and the expression of proteins was determined by Western blotting. The hyperproliferation of VSMC from SHR and overexpression of cyclin D1,cyclin A, cyclin E, cyclin-dependent kinase 2 (cdk2), phosphorylated retinoblastoma protein (pRb), Giα proteins and enhanced phosphorylation of ERK1/2 and AKT exhibited by VSMC from SHR were attenuated by C-ANP4–23 to control levels. In addition, in vivo treatment of SHR with C-ANP4–23 also attenuated the enhanced proliferation of VSMC. Furthemore, PD98059, wortmannin and pertussis toxin, the inhibitors of MAP kinase, PI3kinase and Giα proteins respectively, also attenuated the hyperproliferation of VSMC from SHR and overexpression of cell cycle proteins to control levels. These results indicate that NPR-C activation by C-ANP4–23 attenuates the enhanced levels of cell cycle proteins through the inhibition of enhanced expression of Giα proteins and enhanced activation of MAPkinase/PI3kinase and results in the attenuation of hyperproliferation of VSMC from SHR. It may be suggested that C-ANP4–23 could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension, atherosclerosis and restenosis.
Highlights
Excessive vascular smooth muscle cell (VSMC) proliferation contributes to vascular remodeling that occurs in several vascular disease states including atherosclerosis, hypertension, and diabetes [1]
We have earlier shown that small cytoplasmic domain peptides of natriuretic receptor-C (NPR-C) attenuated the enhanced proliferation of VSMC induced by vasoactive peptides in A10 VSMC [28]
In order to investigate if natriuretic peptide receptors (NPR)-C activation could attenuate the enhanced proliferation of VSMC from spontaneously hypertensive rats (SHR), the effect of various concentrations of C-ANP4–23 on DNA synthesis was examined in VSMC from SHR and WKY rats
Summary
Excessive vascular smooth muscle cell (VSMC) proliferation contributes to vascular remodeling that occurs in several vascular disease states including atherosclerosis, hypertension, and diabetes [1]. We and others reported earlier that VSMC from SHR exhibit exaggerated cell growth (proliferation) compared to VSMC from WKY rats [2,3,4]. The enhanced levels of endogenous vasoactive peptides including Ang II and ET-1 were shown to contribute to the increased expression of Gia proteins and hyperproliferation of VSMC from SHR through the transactivation of EGF-R and MAP kinase signaling pathways [5,6]. The exaggerated growth exhibited by VSMC from SHR was shown to be associated with progression from G1 to S phase in the presence of Ang II and FBS [7,8]. The expression of cell cycle proteins from G1phase that was upregulated in VSMC from SHR [7,9] may contribute to the increased growth
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