TY - JOUR T1 - eNOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 463 LP - 475 DO - 10.1124/jpet.119.264887 VL - 373 IS - 3 AU - Ke Ning AU - Ming-Jie Wang AU - Ge Lin AU - Yi-Lin Zhang AU - Meng-Yao Li AU - Bao-Feng Yang AU - Ying Chen AU - Yong Huang AU - Zhi-Ming Li AU - Yi-Jun Huang AU - Lei Zhu AU - Kun Liang AU - Bo Yu AU - Yi-Zhun Zhu AU - Yi-Chun Zhu Y1 - 2020/06/01 UR - http://jpet.aspetjournals.org/content/373/3/463.abstract N2 - 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.SIGNIFICANCE STATEMENT LEO restored the balance between endothelial NOS and inducible NOS in NO production and inhibited excessive inflammation in atherosclerotic “unstable” and rupture-prone plaques in apolipoprotein E gene–deficient mice. The protective effect of LEO for stabilizing atherosclerotic plaques was due to improved collagen content, increased fibrous cap thickness, and decreased accumulation of macrophages/foam cells. So far, LEO has passed the safety and feasibility test of phase I clinical trial. ER -