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Maslinic acid modulates secreted phospholipase A2-IIA (sPLA2-IIA)-mediated inflammatory effects in macrophage foam cells formation

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Abstract

Secretory phospholipase A2-IIA (sPLA2-IIA) is one of the key enzymes causing lipoprotein modification and vascular inflammation. Maslinic acid is a pentacyclic triterpene which has potential cardioprotective and anti-inflammatory properties. Recent research showed that maslinic acid interacts with sPLA2-IIA and inhibits sPLA2-IIA-mediated monocyte differentiation and migration. This study elucidates the potential of maslinic acid in modulating sPLA2-IIA-mediated inflammatory effects in THP-1 macrophages. We showed that maslinic acid inhibits sPLA2-IIA-mediated LDL modification and suppressed foam cell formation. Further analysis revealed that sPLA2-IIA only induced modest LDL oxidation and that inhibitory effect of maslinic acid on sPLA2-IIA-mediated foam cells formation occurred independently of its anti-oxidative properties. Interestingly, maslinic acid was also found to significantly reduce lipid accumulation observed in macrophages treated with sPLA2-IIA only. Flow cytometry analysis demonstrated that the effect observed in maslinic acid might be contributed in part by suppressing sPLA2-IIA-induced endocytic activity, thereby inhibiting LDL uptake. The study further showed that maslinic acid suppresses sPLA2-IIA-induced up-regulation of PGE2 levels while having no effects on COX-2 activity. Other pro-inflammatory mediators TNF-α and IL-6 were not induced in sPLA2-IIA-treated THP-1 macrophages. The findings of this study showed that maslinic acid inhibit inflammatory effects induced by sPLA2-IIA, including foam cells formation and PGE2 production.

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Authors and Affiliations

  1. School of Biosciences, Taylor’s University, Subang Jaya, Selangor, Malaysia

    Wei Hsum Yap & Bee Kee Ooi

  2. School of Pharmacy, Monash University Malaysia, 47500, Bandar Sunway, Selangor Darul Ehsan, Malaysia

    Nafees Ahmed

  3. Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Bandar Sungai Long, 43000, Kajang, Selangor, Malaysia

    Yang Mooi Lim

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  1. Wei Hsum Yap
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  2. Bee Kee Ooi
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  3. Nafees Ahmed
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  4. Yang Mooi Lim
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Correspondence to Wei Hsum Yap.

Additional information

Communicated by RAJIV K SAXENA.

Corresponding editor: Rajiv K Saxena

Electronic supplementary material

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12038_2018_9745_MOESM1_ESM.tif

Supplementary figure 1. ORO-stained THP-1 macrophages upon incubation with sPLA2-IIA-modified LDL in the presence or absence of maslinic acid. THP-1 macrophages were either (a) non-treated, (b) incubated with native LDL, (c) sPLA2-IIA-modified LDL, (d) sPLA2-IIA -modified LDL with 5 µM maslinic acid, (e) sPLA2-IIA -modified LDL with 10 µM maslinic acid, (f) sPLA2-IIA -modified LDL with 20 µM maslinic acid and (g) sPLA2-IIA -modified LDL with 50 µM maslinic acid. ORO-stained images of THP-1 macrophages in various treatment groups were taken using the NIS Elements AR 3.2 software after 24 h incubation period. (TIFF 1036 kb)

12038_2018_9745_MOESM2_ESM.tif

Supplementary figure 2. ORO-stained THP-1 macrophages upon incubation with sPLA2-IIA enzyme in the presence or absence of maslinic acid. THP-1 macrophages were either (a) non-treated, (b) incubated with sPLA2-IIA enzyme alone, (c) sPLA2-IIA enzyme with 5 µM maslinic acid, (d) sPLA2-IIA enzyme with 10 µM maslinic acid, (e) sPLA2-IIA enzyme with 20 µM maslinic acid and (e) sPLA2-IIA enzyme with 50 µM maslinic acid. ORO-stained images of THP-1 macrophages in various treatment groups were taken using the NIS Elements AR 3.2 software after 24 h incubation period. (TIFF 830 kb)

12038_2018_9745_MOESM3_ESM.tif

Supplementary figure 3. Effects of maslinic acid on CuSO4- and sPLA2-IIA-induced LDL oxidation. LDL were either incubated with 50 µM CuSO4, CuSO4 in the presence of 50 µM maslinic acid, 500 nM sPLA2-IIA, or sPLA2-IIA in the presence of 50 µM maslinic acid for 24 h at 37°C, protected from light and lipid peroxidation was measured using TBARS assay. The TBARS values were representative of mean ± standard deviation from three independent experiments performed in triplicates. Statistical significance was determined using One-way ANOVA followed by a Tukey’s test where several experimental groups were compared to the control group. * represents p<0.05 compared to native LDL; # represents p<0.05 compared to CuSO4-modified LDL; a represents p<0.05 compared to sPLA2-IIA-modified LDL. (TIFF 40 kb)

12038_2018_9745_MOESM4_ESM.tif

Supplementary figure 4. Effects of maslinic acid on sPLA2-IIA-induced TNF-α and IL-6 secretion. THP-1 macrophages were either non-treated, treated with 1 µg/mL sPLA2-IIA, or 1 µg/mL sPLA2-IIA in the presence of 5, 10, 20, and 50 µM maslinic acid for 24 h. TNF-α and IL-6 cytokine secretion levels were measured by ELISA. Statistical significance was determined by One-way ANOVA followed by a Tukey’s test where several experimental groups were compared to the control group. (TIFF 128 kb)

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Yap, W.H., Ooi, B.K., Ahmed, N. et al. Maslinic acid modulates secreted phospholipase A2-IIA (sPLA2-IIA)-mediated inflammatory effects in macrophage foam cells formation. J Biosci 43, 277–285 (2018). https://doi.org/10.1007/s12038-018-9745-6

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