Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 373, Issue 3, Pages 463-475Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.119.264887
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Funding
- Ministry of Science and Technology [2017YFE0120200]
- National Major Scientific and Technological Special Project [2017ZX09301002]
- National Natural Science Foundation of China [81670248, 81970361]
- Innovative Research Team of High-Level Local Universities in Shanghai
- Outstanding Clinical Discipline Project of Shanghai Pudong [PWYgy-2018-08]
- Program for Medical Key Department of Shanghai [ZK2019A10]
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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-kappa B 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-kappa B/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.
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