Régulation du cycle cellulaire par le récepteur natriurétique de type C dans les cellules du muscle lisse vasculaire : mécanismes moléculaires
We have previously shown that natriuretic peptide receptor-C (NPR-C) activation by C-ANP4-23 decreased the proliferation of vascular smooth muscle cells (VSMC) induced by vasoactive peptides (Ang II, ET-1 and AVP). Since, VSMC from SHR also exhibit an enhanced proliferation as compared to VSMC from WKY, we undertook the present study to investigate if C-ANP4-23 could also attenuate the enhanced proliferation of VSMC from SHR and to further explore the underlying mechanisms responsible for this response. The proliferation of VSMC from SHR was significantly increased as compared to VSMC from WKY as determined by [3H]thymidine incorporation and was attenuated by C-ANP4-23 in a concentration-dependent manner. Furthermore the expression of cyclin D1, cyclin-dependent kinase 2 (cdk2) and phosphorylated retinoblastoma protein (pRb) was enhanced in VSMC from SHR compared to WKY which was attenuated by C-ANP4-23. In addition, the inhibitor of cdk4/cyclinD1 (NSC 625987) and cdk2 (NU2058) also attenuated the enhanced proliferation of VSMC from SHR in a concentration-dependent manner. VSMC from SHR also exhibited the enhanced phosphorylation of ERK1/2 and AKT as compared to WKY which was attenuated by C-ANP4-23.. Furthermore, the enhanced expression of cyclin D1, cdk2 and pRb in VSMC from SHR were also attenuated by pertussis toxin that inactivates Giα protein, PD 98095, a MEK kinase inhibitor, wortmannin, PI3K inhibitor as well as by losartan, an AT1 receptor antagonist. These results suggest that NPR-C activation attenuates the enhanced proliferation of VSMC from SHR which may be attributed to Giα /MAP kinase/PI3K-mediated inhibition of the expression of cell cycle components.
hypertension SHR NPR-C Gi AKT cell cycle