SCM-198 attenuates early atherosclerotic lesions in hypercholesterolemic rabbits via modulation of the inflammatory and oxidative stress pathways

Objective: To investigate SCM-198 (also known as leonurine), a compound in Herba leonuri, as well as its effect on the progression of atherosclerosis in hypercholesterolemic rabbits and underlying mechanisms. Methods: Thirty New Zealand male White rabbits (5 groups, n = 6) were fed either a normal diet or a high-cholesterol diet (1%). The rabbits on the high-cholesterol diet received treatments of low, moderate, and high doses of SCM-198 and placebo concurrently. Eight weeks later, the animals underwent ultrasonographic imaging. They were then sacrificed for further pathological and molecular biological analysis. Results: SCM-198-treated rabbits showed a significant alleviation in the development of atherosclerosis in a dose-dependent manner. The lesions were smaller after the SCM-198 treatments. In addition, the elasticity of the arteries and hemodynamic status improved, accompanied with a decrease in smooth muscle cell migration and, macrophage infiltration, as well as the expression of platelet-endothelial cell adhesion molecule-1 (PECAM-1) in the aortas. Marginal changes in the lipid parameters were found in the SCM-198-treated rabbits, with high-density lipid cholesterol (HDL-C) elevation and triglyceride (TG) reduction at the high dose. SCM-198 treatment dose-dependently reduced levels of serum soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), as well as the mRNA levels of VCAM-1, IL-6, TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), iNOS and MMP-9 in the aorta. In addition, SCM-198 also dose-dependently increased the total antioxidant capacities and in parallel decreased the lipid peroxidation levels in the serum and liver. The antioxidant effects of SCM-198 were implicated by the enhanced activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and levels of glutathione (GSH) in the liver, as well as the mRNA levels of CAT, SOD-1 and GPx in the aorta. Conclusions: In a rabbit atherosclerotic model, SCM-198 dose-dependently ameliorated the progression of atherosclerotic lesions and vascular dysfunction accompanied by the suppression of inflammatory factors and oxidative stress. These findings suggested that SCM-198 might be a potential agent for the treatment of atherosclerosis. Crown Copyright (c) 2012 Published by Elsevier Ireland Ltd. All rights reserved.