Pseudolaric acid B attenuates atherosclerosis progression and inflammation by suppressing PPARγ-mediated NF-κB activation.

Abstract

AIMS/OBJECTIVE:

Atherosclerosis is a progressive disease of large arteries characterized with chronic inflammation and aberrant immune response. Pseudolaric acid B (PB) has been found to exert multiple effects by inhibiting inflammatory response. However, there is no comprehensive assessment of the effects of PB on atherosclerosis using relevant in vivo and in vitro models.

MATERIAL AND METHODS:

Male ApoE-/- mice were treated with PB orally with a high fat diet (HFD) to clarify its anti-atherosclerotic activities. RAW264.7 macrophage line, a well-accepted cell model of atherosclerosis, was used to investigate anti-inflammatory effects and molecular mechanisms of PB.

RESULTS:

PB significantly attenuated atherosclerotic lesions by modulating plasma lipid profiles as well as inhibiting inflammatory responses in macrophages of atherosclerotic mice. Meanwhile, PB markedly suppressed the expression of pro-inflammatory cytokines, and regulated cholesterol efflux related genes in oxidative low density lipoprotein (ox-LDL)-loaded macrophages. The cellular uptake of Dil-labeled ox-LDL was significantly inhibited by PB either. Moreover, the ability of PB to suppress nuclear factor kappa B (NF-κB) and activate peroxisome proliferator-activated receptor gamma (PPARγ) was confirmed using luciferase reporter assays. Conversely, the selective PPARγ antagonist GW9662 reversed the influence of PB in macrophages.

CONCLUSION:

Together, these findings indicate that PB exerts its protective effects on atherosclerosis by inhibiting macrophage-mediated inflammatory response and cellular ox-LDL uptake, and promoting cholesterol efflux by suppressing NF-κB activation PPARγ-dependently. Therefore, PB may be a promising agent for inflammatory and atherosclerotic diseases.

• Authors: Tan Li, Wei Wang, Yu-Xiu Li, Xiao Li, Wen-Jie Ji, Yong-Qiang Ma, Hong Chen, Ji-Hong Zhao, Xin Zhou
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 59 Pg. 76-85 (Jun 2018) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 29631101 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Anti-Inflammatory Agents
• Diterpenes
• IL1B protein, mouse
• Interleukin-1beta
• Lipoproteins, LDL
• NF-kappa B
• PPAR gamma
• Tumor Necrosis Factor-alpha
• oxidized low density lipoprotein
• pseudolaric acid B

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Aorta (drug effects, metabolism)
• Atherosclerosis (blood, drug therapy, metabolism)
• Diet, High-Fat
• Disease Progression
• Diterpenes (pharmacology, therapeutic use)
• Interleukin-1beta (blood, genetics)
• Lipid Metabolism (drug effects)
• Lipoproteins, LDL (metabolism)
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• NF-kappa B (metabolism)
• PPAR gamma (metabolism)
• RAW 264.7 Cells
• Tumor Necrosis Factor-alpha (blood, genetics)