eNOS-nitric oxide system contributes to a novel antiatherogenic effect of leonurine via inflammation inhibition and plaque stabilization

Abstract

Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system and prevents the early progression of atherosclerosis; however, it is not clear whether LEO is effective for plaque stability. A novel mouse atherosclerosis model involving tandem stenosis (TS) of the right carotid artery combined with western diet (WD) feeding was used. Apolipoprotein E gene-deficient mice were fed with a WD and received LEO administration daily for 13 weeks. TS was introduced 6 weeks after the onset of experiments. We found that LEO enhanced plaque stability by increasing fibrous cap thickness and collagen content while decreasing the population of CD68-positive cells. Enhanced plaque stability by LEO was associated with the nitric oxide synthase (NOS)-nitric oxide (NO) system. LEO restored the balance between endothelial NOS(E)-and inducible NOS(iNOS)-derived NO production; suppressed the NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque, including cytokine interleukin 6; and downregulated the expression of adhesion molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with oxidized low-density lipoprotein-challenged human umbilical vein endothelial cells revealed that LEO balanced NO production and inhibited NF-κB/P65 nuclear translocation, thus mitigating inflammation. In conclusion, the restored balance of the NOS-NO system and mitigated inflammation contribute to the plaque-stabilizing effect of LEO.