Sodium nitroprusside attenuates hyperproliferation of vascular smooth muscle cells from spontaneously hypertensive rats through the inhibition of overexpression of AT1 receptor, cell cycle proteins, and c-Src/growth factor receptor signaling pathways.

We recently showed that sodium nitroprusside (SNP), a NO donor, attenuated hypertension in spontaneously hypertensive rats (SHR). Since hypertension is associated with enhanced proliferation and hypertrophy of vascular smooth muscle cells (VSMC), the present study examines whether in vivo treatment of SHR with SNP could also inhibit the augmented proliferation of VSMC and explore the signaling mechanisms. Treatment of 8 week old SHR and Wistar Kyoto rats with SNP twice a week for 2 weeks inhibited the enhanced proliferation of VSMC from SHR, the enhanced expression of angiotensin II type 1 (AT1) receptor, and enhanced activation of c-Src and growth factor receptors and ERK1/2 signaling pathways. In addition, SNP also inhibited the overexpression of cell cycle proteins including cyclins D1, Cdk4, and phosphorylated pRB and restored the downregulated Cdk inhibitors p21Cip1 and p27Kip1 expression towards control levels. Furthermore, SNP-induced inhibition of enhanced levels of the AT1 receptor and enhanced proliferation was reversed by L-NAME, an inhibitor of nitric oxide synthase. These results suggest that the SNP-induced antiproliferative effect may be mediated through the inhibition of enhanced expression of the AT1 receptor, cell cycle proteins and activation of c-Src, growth factor receptors, and MAP kinase signaling.