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Research ArticleCardiovascular

eNOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization

Ke Ning, Ming-Jie Wang, Ge Lin, Yi-Lin Zhang, Meng-Yao Li, Bao-Feng Yang, Ying Chen, Yong Huang, Zhi-Ming Li, Yi-Jun Huang, Lei Zhu, Kun Liang, Bo Yu, Yi-Zhun Zhu and Yi-Chun Zhu
Journal of Pharmacology and Experimental Therapeutics June 2020, 373 (3) 463-475; DOI: https://doi.org/10.1124/jpet.119.264887
Ke Ning
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Ming-Jie Wang
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Ge Lin
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Yi-Lin Zhang
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Meng-Yao Li
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Bao-Feng Yang
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Ying Chen
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Yong Huang
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Zhi-Ming Li
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Yi-Jun Huang
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Lei Zhu
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Kun Liang
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Bo Yu
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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Yi-Zhun Zhu
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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  • For correspondence: yzzhu@must.edu.mo
Yi-Chun Zhu
Shanghai Key Laboratory of Bioactive Small Molecules and Shanghai Key Laboratory of Clinical Geriatric Medicine, Department of Physiology and Pathophysiology, Shanghai Medical College, School of Basic Medical Sciences (K.N., M.-J.W., G.L., Y.-L.Z., M.-Y.L., Y.C., Y.H., Z.-M.L., Y.-C.Z.), Department of Vascular Surgery, Huashan Hospital (Y.-J.H., L.Z., K.L., B.Y.), and Institutes of Science and Technology for Brain-inspired intelligence (B.-F.Y.), Fudan University, Shanghai, China; and State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China (Y.-Z.Z.)
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  • For correspondence: yczhu@shmu.edu.cn
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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.

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.

Footnotes

    • Received December 31, 2019.
    • Accepted March 18, 2020.
  • ↵3 K.N. and M.-J.W. contributed equally to this work.

  • This work was supported by grants from the Ministry of Science and Technology (2017YFE0120200), National Major Scientific and Technological Special Project (No. 2017ZX09301002), the National Natural Science Foundation of China (Grant 81670248, 81970361), funding of the Innovative Research Team of High-Level Local Universities in Shanghai, the Outstanding Clinical Discipline Project of Shanghai Pudong (PWYgy-2018-08) and the Program for Medical Key Department of Shanghai (ZK2019A10).

  • https://doi.org/10.1124/jpet.119.264887.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 373 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 373, Issue 3
1 Jun 2020
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Research ArticleCardiovascular

LEO Reduces Atherosclerosis and Enhances Plaque Stability

Ke Ning, Ming-Jie Wang, Ge Lin, Yi-Lin Zhang, Meng-Yao Li, Bao-Feng Yang, Ying Chen, Yong Huang, Zhi-Ming Li, Yi-Jun Huang, Lei Zhu, Kun Liang, Bo Yu, Yi-Zhun Zhu and Yi-Chun Zhu
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 463-475; DOI: https://doi.org/10.1124/jpet.119.264887

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Research ArticleCardiovascular

LEO Reduces Atherosclerosis and Enhances Plaque Stability

Ke Ning, Ming-Jie Wang, Ge Lin, Yi-Lin Zhang, Meng-Yao Li, Bao-Feng Yang, Ying Chen, Yong Huang, Zhi-Ming Li, Yi-Jun Huang, Lei Zhu, Kun Liang, Bo Yu, Yi-Zhun Zhu and Yi-Chun Zhu
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 463-475; DOI: https://doi.org/10.1124/jpet.119.264887
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