Advertisement

Journal of Biosciences

, Volume 43, Issue 2, pp 277–285 | Cite as

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

  • Wei Hsum Yap
  • Bee Kee Ooi
  • Nafees Ahmed
  • Yang Mooi Lim
Article
  • 56 Downloads

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.

Keywords

COX-2 endocytosis foam cells maslinic acid PGE2 sPLA2-IIA 

Notes

Supplementary material

12038_2018_9745_MOESM1_ESM.tif (1 mb)
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 (830 kb)
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 (41 kb)
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 (129 kb)
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)

References

  1. Allouche Y, Beltrán G, Gaforio JJ, Uceda M, Mesa MD 2010 Antioxidant and antiatherogenic activities of pentacyclic triterpenic diols and acids. Food Chem. Toxicol. 48 2885–2890CrossRefPubMedGoogle Scholar
  2. Aviram M 1999 Macrophage foam cell formation during early atherogenesis is determined by the balance between pro-oxidants and anti-oxidants in arterial cells and blood lipoproteins. Antioxid. Redox Sign. 1 585–594CrossRefGoogle Scholar
  3. Bidgood MJ, Jamal OS, Cunningham AM, Brooks PM and Scott KF 2000 Type IIA secretory phospholipase A2 up-regulates cyclooxygenase-2 and amplifies cytokine-mediated prostaglandin production in human rheumatoid synoviocytes. J. Immunol. 165 2790–2797CrossRefPubMedGoogle Scholar
  4. Bryant KJ, Bidgood MJ, Lei PW, Taberner M, Salom C, Kumar V, Lee L, Church WB, Courtenay B, Smart BP, Gelb MH, Cahill MA, Graham GG, McNeil HP and Scott KF 2011 A bifunctional role for group IIA secreted phospholipase A2 in human rheumatoid fibroblast-like synoviocyte arachidonic acid metabolism. J. Biol. Chem. 286 2492–2503CrossRefPubMedGoogle Scholar
  5. Cupillard L, Koumanov K, Mattéi MG, Lazdunski M and Lambeau G 1997 Cloning, chromosomal mapping, and expression of a novel human secretory phospholipase A2. J. Biol. Chem. 272 15745–15752CrossRefPubMedGoogle Scholar
  6. Curfs DM, Ghesquiere SA, Vergouwe MN, van der Made I, Gijbels MJ, Greaves DR, Verbeek JS, Hofker MH and de Winther MP 2008 Macrophage secretory phospholipase A2 group X enhances anti-inflammatory responses, promotes lipid accumulation, and contributes to aberrant lung pathology. J. Biol. Chem. 283 21640–21648CrossRefPubMedGoogle Scholar
  7. Deutsch MJ, Schriever SC, Roscher AA and Ensenauer R 2014 Digital image analysis approach for lipid droplet size quantitation of Oil Red O-stained cultured cells. Anal. Biochem. 445 87–89CrossRefPubMedGoogle Scholar
  8. Esterbauer H, Wäg G and Puhl H 1993 Lipid peroxidation and its role in atherosclerosis. Br. Med. Bull. 49 566–576CrossRefPubMedGoogle Scholar
  9. Fernández-Navarro M, Peragón J, Esteban FJ, Amores V, Higuera M and Lupiáñez JA 2010 Olives and olives oil in cancer prevention (Elsevier Inc.)Google Scholar
  10. George SJ and Johnson J 2010 Atherosclerosis: Molecular and cellular mechanisms (John Wiley & Sons)Google Scholar
  11. Ghesquiere SA, Gijbels MJ, Anthonsen M, van Gorp PJ, van der Made I, Johansen B, Hofker MH and de Winther MP 2005 Macrophage—specific overexpression of group IIA sPLA2 increases atherosclerosis and enhances collagen deposition. J. Lipid Res. 46 201–209CrossRefPubMedGoogle Scholar
  12. Hilgendorf I, Swirski FK and Robbins CS 2015 Monocyte fate in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 35 272–279CrossRefPubMedGoogle Scholar
  13. Huang L, Guan T, Qian Y, Huang M, Tang X, Li Y and Sun H 2011 Anti-inflammatory effects of maslinic acid, a natural triterpene, in cultured cortical astrocytes via suppression of nuclear factor-kappa B. Eur. J. Pharmacol. 672 169–174CrossRefPubMedGoogle Scholar
  14. Hurt-Camejo E, Andersen S, Standal R, Rosengren B, Sartipy P, Stadberg E and Johansen B 1997 Localization of nonpancreatic secretory phospholipase A2 in normal and atherosclerotic arteries. Activity of the isolated enzyme on low-density lipoproteins. Arterioscler. Thromb. Vasc. Biol. 17 300–309CrossRefPubMedGoogle Scholar
  15. Ibeas E, Fuentes L, Martín R, Hernández M and Nieto ML 2009 Secreted phospholipase A2 type IIA as a mediator connecting innate and adaptive immunity: new role in atherosclerosis. Cardiovasc. Res. 81 54–63CrossRefPubMedGoogle Scholar
  16. Itabe H, Obama T and Kato R 2011 The dynamics of oxidized LDL during atherogenesis. J. Lipid. Article ID 418313Google Scholar
  17. Ivandic B, Castellani LW, Wang XP, Qiao JH, Mehrabian M, Navab M, Fogelman AM, Grass DS, Swanson ME, de Beer MC, de Beer F and Lusis AJ 1999 Role of Group II secretory phospholipase A2 in atherosclerosis Arterioscler. Thromb. Vasc. Biol. 19 1284–1290CrossRefPubMedGoogle Scholar
  18. Kruth HS, Jones NL, Huang W, Zhao B, Ishii I, Chang J, Combs CA, Malide D and Zhang WY 2005 Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein. J. Biol. Chem. 280 2352–2360CrossRefPubMedGoogle Scholar
  19. Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, Rhee JS, Silverstein R, Hoff HF and Freeman MW 2002 Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem. 277 49982–49988CrossRefPubMedGoogle Scholar
  20. Lozano-Mena G, Sanchez-Gonzalez M, Juan ME and Planas JM 2014 Maslinic Acid, a natural phytoalexin-type triterpene from olives—a promising nutraceutical? Molecules 19 11538–11559CrossRefPubMedGoogle Scholar
  21. Mehta JL 2004 The role of LOX-1, a novel lectin-like receptor for oxidized low density lipoprotein, in atherosclerosis. Can. J. Cardiol. 20 32B–36BPubMedGoogle Scholar
  22. Montilla M, Agil A, Navarro M, Jimenez M, Granados A, Parra A and Cabo MM 2003 Antioxidant activity of maslinic acid, a triterpene derivative obtained from Olea europaea. Planta Med. 69 472–474CrossRefPubMedGoogle Scholar
  23. Murakami M, Taketomi Y, Girard C, Yamamoto K and Lambeau G 2010 Emerging roles of secreted phospholipase A2 enzymes: Lessons from transgenic and knockout mice. Biochimie 92 561–582CrossRefPubMedGoogle Scholar
  24. Neuzil J, Upston JM, Witting PK, Scott KF and Stocker R 1998 Secretory phospholipase A2 and lipoprotein lipase enhance 15-lipoxygenase-induced enzymic and nonenzymic lipid peroxidation in low-density lipoproteins. Biochemistry 37 9203–9210CrossRefPubMedGoogle Scholar
  25. Prades J, Vögler O, Alemany R, Gomez-Florit M, Funari SS, Ruiz- Gutierrez V and Barcel F 2011 Plant pentacyclic triterpenic acids as modulators of lipid membrane physical properties. Biochim. Biophys. Acta 1808 752–760CrossRefPubMedGoogle Scholar
  26. Pruzanski W, Stefanski E, de Beer FC, de Beer MC, Vadas P, Ravandi A and Kuksis A 1998 Lipoproteins are substrates for human secretory group IIA phospholipase A2: preferential hydrolysis of acute phase HDL. J. Lipid Res. 39 2150–2160PubMedGoogle Scholar
  27. Rosenson RS and Gelb MH 2009 Secretory Phospholipase A2: A multifaceted family of proatherogenic enzymes. Curr. Cardiol. Rep. 11 445–451CrossRefPubMedGoogle Scholar
  28. Rosenson RS and Hurt-Camejo E 2012 Phospholipase A2 enzymes and the risk of atherosclerosis. Eur. Heart J. 33 2899–2909CrossRefPubMedGoogle Scholar
  29. Sparrow CP, Parthasarathy S and Steinberg D 1988 Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell-mediated oxidative modification. J. Lipid Res. 29 745–753PubMedGoogle Scholar
  30. Stocker R and Keaney Jr JF 2004 Role of oxidative modifications in atherosclerosis. Physiol. Rev. 84 1381–1478CrossRefPubMedGoogle Scholar
  31. Tellis CC and Tselepis AD 2009 The role of lipoprotein-associated phospholipase A2 in atherosclerosis may depend on its lipoprotein carrier in plasma. Biochim. Biophys. Acta 1791 327–338CrossRefPubMedGoogle Scholar
  32. Tietge UJ, Pratico D, Ding T, Funk CD, Hildebrand RB, Van Berkel TJ and Van Eck M 2005 Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress J. Lipid Res. 46 1604–1614CrossRefPubMedGoogle Scholar
  33. Xu S, Huang Y, Xie Y, Lan T, Le K, Chen J, Chen S, Gao S, Xu X, Shen X, Huang H and Liu P 2010 Evaluation of foam cell formation in cultured macrophages: an improved method with Oil Red O staining and DiI-oxLDL uptake. Cytotechnology 62 473–481CrossRefPubMedPubMedCentralGoogle Scholar
  34. Yap WH and Lim YM 2015 Mechanistic perspectives of maslinic acid in targeting inflammation. Biochem. Res. Int. 2015 1–9CrossRefGoogle Scholar
  35. Yap WH, Ahmed N and Lim YM 2016 Inhibition of human group IIA-secreted phospholipase A2 and THP-1 monocyte recruitment by maslinic acid. Lipids 51 1153CrossRefPubMedGoogle Scholar
  36. Yla-Herttuala S, Rosenfeld ME, Parthasarathy S, Glass CK, Sigal E, Witztum JL and Steinberg D 1990 Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions. Proc. Natl. Acad. Sci. USA 87 6959–6963CrossRefPubMedPubMedCentralGoogle Scholar
  37. Zamora R, Vodovotz Y and Billiar TR 2000 Inducible nitric oxide synthase and inflammatory diseases. Mol. Med. 6 347–373PubMedPubMedCentralGoogle Scholar

Copyright information

© Indian Academy of Sciences 2018

Authors and Affiliations

  1. 1.School of BiosciencesTaylor’s UniversitySubang JayaMalaysia
  2. 2.School of PharmacyMonash University MalaysiaBandar SunwayMalaysia
  3. 3.Department of Pre-Clinical Sciences, Faculty of Medicine and Health SciencesUniversiti Tunku Abdul RahmanKajangMalaysia

Personalised recommendations