TY - JOUR T1 - Elevation of intracellular levels of nitric oxide in SHR attenuates hyperproliferation of vascular smooth muscle cells through the inhibition of AT1 receptor expression and c-Src/growth factor receptor signaling pathways JF - bioRxiv DO - 10.1101/474163 SP - 474163 AU - Ekhtear Hossain AU - Oli Sarkar AU - Yuan Li AU - Madhu B. Anand-Srivastava Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/11/19/474163.abstract N2 - We previously showed that decreased levels of intracellular nitric oxide (NO) contribute to the hyperproliferation of vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR). The present study investigates if elevation of intracellular levels of NO by in vivo treatment of SHR with NO donor, sodium nitroprusside (SNP) that was shown to attenuate hypertension could attenuate the hyperproliferation of VSMC and identify the molecular mechanisms. Intraperitoneal injection of SNP (0.5 mg/kg BW) into 8-week-old SHR and WKY rats twice a week for two weeks increased significantly the intracellular levels of NO in aortic VSMC and resulted in the attenuation of hyperproliferation of VSMC from SHR to control levels. The antiproliferative effect of SNP was associated with the restoration of the overexpression of cell cycle proteins, cyclins D1, E, Cdk2, Cdk4, phosphorylated pRB and decreased expression of Cdk inhibitors p21Cip1 and p27Kip1 towards control levels. In addition, SNP treatment also attenuated the overexpression of angiotensin II receptor type 1 (AT1) receptor, phosphorylation of c-Src, EGF-R, PDGF-R, IGF-IR and ERK1/2 in VSMC from SHR to control levels. These results suggest that the augmentation of intracellular levels of NO elicits antiproliferative effect that may be mediated through its ability to inhibit the enhanced expression of AT1 receptor, activation of c- Src, growth factor receptors and MAP kinase signaling and overexpression of cell cycle proteins.AbbreviationsSNPsodium nitroprussideODQH (1, 2, 4) oxadiazole (4, 3-a) quinoxalin-1-oneAng IIangiotensin IIAT1 receptorangiotensin II type 1 receptorET-1endothelin-1WKY ratWistar-Kyoto ratSHRspontaneously hypertensive ratsEGFRepidermal growth factor receptorPDGFRplatelet-derived growth factor receptorIGF-IRinsulin-like growth factor 1 (IGF-1) receptor ER -