Imperatorin derivative OW1, a new vasoactive compound, attenuates cell proliferation and migration by inhibiting Nox1-mediated oxidative stress

Abstract Background: Vascular remodeling is the common pathological basis of cardiovascular and cerebrovascular diseases. In previous studies, we identified a new imperatorin derivative, OW1, that had significant effects on vasodilation and inhibited vascular remodeling. OW1 reduced blood pressure and microvascular remodeling in thoracic aorta, heart, and kidney, and inhibited peroxide levels in serum from hypertensive rats. Blood shear stress and Ang II induced increases in ROS levels that were dependent on Nox1 activation. In the present study, we investigated whether OW1 could inhibit vascular cell proliferation and migration through attenuation of Nox1-ROS signaling. Methods and results: OW1 (1, 3, 10 µmol/L) inhibited Ang II-induced increases in peroxidation levels (LPO, SOD and ROS levels) in VSMCs and HUVECs. Ang II-induced increases in mRNA and protein levels of Noxs (Nox1, p22phox, p47phox, NoxA1/p67phox, and Nox2/gp91phox) in VSMCs and HUVECs were also inhibited by OW1. Besides, OW1 attenuated cell proliferation and migration through the MAPK pathway and MMPs in HUVEC. However, OW1 treatment had no significant effects on cell migration, ROS levels and the expression of phosphorylated MAPKs in VSMCs when Nox1 gene knockout. OW1-mediated downregulation of ROS levels and the expression of phosphorylated MAPKs in NIH3T3 cells with a Nox1 overexpression plasmid. Conclusion: The present study demonstrated that Ang II induced VSMC/HUVEC proliferation and migration via increases in Nox1 and intracellular peroxide levels. OW1 might inhibit vascular remodeling through downregulation of the Nox1-ROS-MAPK/MMP signaling pathways. OW1 is expected to serve as a new therapeutic target associated with peroxide levels for the treatment of cardiovascular diseases.