RT Journal Article
SR Electronic
T1 eNOS-NO system contributes to a novel anti-atherogenic effect of Leonurine via inflammation inhibition and plaque stabilization
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.264887
DO 10.1124/jpet.119.264887
A1 Ke Ning
A1 Ming-Jie Wang
A1 Ge Lin
A1 Yi-Lin Zhang
A1 Meng-Yao Li
A1 Bao-Feng Yang
A1 Ying Chen
A1 Yong Huang
A1 Zhi-Ming Li
A1 Yi-Jun Huang
A1 Lei Zhu
A1 Kun Liang
A1 Bo Yu
A1 Yi-Zhun Zhu
A1 Yi-Chun Zhu
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/04/01/jpet.119.264887.abstract
AB Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system. It 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. ApoE -/- 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 NOS-NO system. LEO restored the balance between eNOS and iNOS derived NO production; suppressed NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque including cytokine IL-6 and downregulated the expression of adhesion moleculars molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with ox-LDL challenged HUVECs 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 syestem and mitigated inflammation contribute to the plaque stabilizing effect of LEO.SIGNIFICANCE STATEMENT LEO restored the balance between eNOS and iNOS in NO production, and inhibited excessive inflammation in atherosclerotic "unstable" and rupture-prone plaques in ApoE-/- 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.