In vitro evaluation of the involvement of Nrf2 in maslinic acid-mediated anti-inflammatory effects in atheroma pathogenesis

Ooi BK 1 , Phang SW 1 , Yong PVC 1 , Chellappan DK 2 , Dua K 3 , Khaw KY 4 Show all authors , Goh BH 5 , Pusparajah P 6 , Yap WH 7

Affiliations 

  • 1 School of Biosciences, Taylor's University, Subang Jaya, Selangor Darul Ehsan 47500, Malaysia
  • 2 Department of Life Sciences, School of Pharmacy, International Medical University (IMU), Bukit Jalil, 57000, Kuala Lumpur, Malaysia
  • 3 Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
  • 4 Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia
  • 5 Biofunctional Molecule Exploratory Research Group, School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: goh.bey.hing@monash.edu
  • 6 Medical Health and Translational Research Group, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia. Electronic address: priyia.pusparajah@monash.edu
  • 7 School of Biosciences, Taylor's University, Subang Jaya, Selangor Darul Ehsan 47500, Malaysia; Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences (FHMS), Taylor's University, Subang Jaya 47500, Malaysia. Electronic address: weihsum.yap@taylors.edu.my
Life Sci, 2021 Aug 01;278:119658.
PMID: 34048809 DOI: 10.1016/j.lfs.2021.119658

Abstract

AIMS: Maslinic acid (MA) is a naturally occurring pentacyclic triterpene known to exert cardioprotective effects. This study aims to investigate the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) for MA-mediated anti-inflammatory effects in atheroma pathogenesis in vitro, including evaluation of tumor necrosis factor-alpha (TNF-α)-induced monocyte recruitment, oxidized low-density lipoprotein (oxLDL)-induced scavenger receptors expression, and nuclear factor-kappa B (NF-ĸB) activity in human umbilical vein endothelial cells (HUVECS) and human acute monocytic leukemia cell line (THP-1) macrophages.

MATERIALS AND METHODS: An in vitro monocyte recruitment model utilizing THP-1 and HUVECs was developed to evaluate TNF-α-induced monocyte adhesion and trans-endothelial migration. To study the role of Nrf2 for MA-mediated anti-inflammatory effects, Nrf2 inhibitor ML385 was used as the pharmacological inhibitor. The expression of Nrf2, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 36 (CD36), and scavenger receptor type A (SR-A) in HUVECs and THP-1 macrophages were investigated using RT-qPCR and Western blotting. The NF-κB activity was determined using NF-κB (p65) Transcription Factor Assay Kit.

KEY FINDINGS: The results showed opposing effects of MA on Nrf2 expression in HUVECs and THP-1 macrophages. MA suppressed TNF-α-induced Nrf2 expression in HUVECs, but enhanced its expression in THP-1 macrophages. Combined effects of MA and ML385 suppressed MCP-1, VCAM-1, and SR-A expressions. Intriguingly, at the protein level, ML385 selectively inhibited SR-A but enhanced CD36 expression. Meanwhile, ML385 further enhanced MA-mediated inhibition of NF-κB activity in HUVECs. This effect, however, was not observed in THP-1 macrophages.

SIGNIFICANCE: MA attenuated foam cell formation by suppressing VCAM-1, MCP-1, and SR-A expression, as well as NF-κB activity, possibly through Nrf2 inhibition. The involvement of Nrf2 for MA-mediated anti-inflammatory effects however differs between HUVECs and macrophages. Future investigations are warranted for a detailed evaluation of the contributing roles of Nrf2 in foam cells formation.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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