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      Secreted phospholipase A 2, lipoprotein hydrolysis, and atherosclerosis: integration with lipidomics

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          Abstract

          Phospholipase A 2 (PLA 2) is a group of enzymes that hydrolyze the sn-2 position of glycerophospholipids to yield fatty acids and lysophospholipids. Of many PLA 2s or related enzymes identified to date, secreted PLA 2s (sPLA 2s) comprise the largest family that contains 10 catalytically active isozymes. Besides arachidonic acid released from cellular membranes for eicosanoid synthesis, several if not all sPLA 2s have recently been implicated in hydrolysis of phospholipids in lipoprotein particles. The sPLA 2-processed low-density lipoprotein (LDL) particles contain a large amount of lysophospholipids and exhibit the property of “small-dense” or “modified” LDL, which facilitates foam cell formation from macrophages. Transgenic overexpression of these sPLA 2s leads to development of atherosclerosis in mice. More importantly, genetic deletion or pharmacological inhibition of particular sPLA 2s significantly attenuates atherosclerosis and aneurysm. In this article, we will give an overview of current understanding of the role of sPLA 2s in atherosclerosis, with recent lipidomics data showing the action of a subset of sPLA 2s on lipoprotein phospholipids.

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          Biochemistry and physiology of mammalian secreted phospholipases A2.

          Gérard Lambeau, Michael Gelb (2007)
          Phospholipases A(2) (PLA2s) are esterases that hydrolyze the sn-2 ester of glycerophospholipids and constitute one of the largest families of lipid hydrolyzing enzymes. The mammalian genome contains 10 enzymatically active secreted PLA2s (sPLA2s) and two sPLA2-related proteins devoid of lipolytic enzymatic activity. In addition to the well-established functions of one of these enzymes in digestion of dietary phospholipids and another in host defense against bacterial infections, accumulating evidence shows that some of these sPLA2s are involved in arachidonic acid release from cellular phospholipids for the biosynthesis of eicosanoids, especially during inflammation. More speculative results suggest the involvement of one or more sPLA2s in promoting atherosclerosis and cancer. In addition, the mammalian genome encodes several types of sPLA2-binding proteins, and mounting evidence shows that sPLA2s may have functions related to binding to cellular target proteins in a manner independent of their lipolytic enzymatic activity.
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            Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells.

            Nathan Schwartz, F Parhami, J. Berliner … (1990)
            After exposure to low density lipoprotein (LDL) that had been minimally modified by oxidation (MM-LDL), human endothelial cells (EC) and smooth muscle cells (SMC) cultured separately or together produced 2- to 3-fold more monocyte chemotactic activity than did control cells or cells exposed to freshly isolated LDL. This increase in monocyte chemotactic activity was paralleled by increases in mRNA levels for a monocyte chemotactic protein 1 (MCP-1) that is constitutively produced by the human glioma U-105MG cell line. Antibody that had been prepared against cultured baboon smooth muscle cell chemotactic factor (anti-SMCF) did not inhibit monocyte migration induced by the potent bacterial chemotactic factor f-Met-Leu-Phe. However, anti-SMCF completely inhibited the monocyte chemotactic activity found in the media of U-105MG cells, EC, and SMC before and after exposure to MM-LDL. Moreover, monocyte migration into the subendothelial space of a coculture of EC and SMC that had been exposed to MM-LDL was completely inhibited by anti-SMCF. Anti-SMCF specifically immunoprecipitated 10-kDa and 12.5-kDa proteins from EC. Incorporation of [35S]methionine into the immunoprecipitated proteins paralleled the monocyte chemotactic activity found in the medium of MM-LDL stimulated EC and the levels of MCP-1 mRNA found in the EC. We conclude that (i) SMCF is in fact MCP-1 and (ii) MCP-1 is induced by MM-LDL.
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              Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice.

              S. Fazio, W. Funk, T Cyrus … (1999)
              Atherosclerosis may be viewed as an inflammatory disease process that includes early oxidative modification of LDLs, leading to foam cell formation. This "oxidation hypothesis" has gained general acceptance in recent years, and evidence for the role of lipoxygenases in initiation of, or participation in, the oxidative process is accumulating. However, the relative contribution of macrophage-expressed lipoxygenases to atherogenesis in vivo remains unknown. Here, we provide in vivo evidence for the role of 12/15-lipoxygenase in atherogenesis and demonstrate diminished plasma IgG autoantibodies to oxidized LDL epitopes in 12/15-lipoxygenase knockout mice crossbred with atherosclerosis-prone apo E-deficient mice (apo E-/-/L-12LO-/-). In chow-fed 15-week-old apo E-/-/L-12LO-/- mice, the extent of lesions in whole-aorta en face preparations (198 +/- 60 microm2) was strongly reduced (P < 0.001, n = 12) when compared with 12/15-lipoxygenase-expressing controls (apo E-/-/L-12LO+/+), which showed areas of lipid deposition (15,700 +/- 2,688 microm2) in the lesser curvature of the aortic arch, branch points, and in the abdominal aorta. These results were observed despite cholesterol, triglyceride, and lipoprotein levels that were similar to those in apo E-deficient mice. Evidence for reduced lesion development was observed even at 1 year of age in apo E-/-/L-12LO-/- mice. The combined data indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and suggest that inhibition of this enzyme may decrease disease progression.
              Article 0 comments Cited 64 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : +81-3-53163228 , +81-3-53163125 , murakami-mk@igakuken.or.jp
                Journal
                Journal ID (nlm-ta): Anal Bioanal Chem
                Title: Analytical and Bioanalytical Chemistry
                Publisher: Springer-Verlag (Berlin/Heidelberg )
                ISSN (Print): 1618-2642
                ISSN (Electronic): 1618-2650
                Publication date (Electronic): 29 March 2011
                Publication date PMC-release: 29 March 2011
                Publication date (Print): June 2011
                Volume: 400
                Issue: 7
                Pages: 1829-1842
                Affiliations
                Lipid Metabolism Project, The Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156–8506 Japan
                Article
                Publisher ID: 4864
                DOI: 10.1007/s00216-011-4864-z
                PMC ID: 3098357
                PubMed ID: 21445663
                SO-VID: 7461a820-38ca-4cf1-8b01-ec41b9d31605
                Copyright © © The Author(s) 2011
                History
                Date received : 27 November 2010
                Date revision received : 14 February 2011
                Date accepted : 1 March 2011
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © Springer-Verlag 2011

                ScienceOpen disciplines: Analytical chemistry
                Keywords: enzymes,mass spectrometry,lipids
                Data availability:
                ScienceOpen disciplines: Analytical chemistry
                Keywords: enzymes, mass spectrometry, lipids

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