doi: 10.1161/01.ATV.0000258412.58289.ee
© 2007 American Heart Association, Inc.
Editorials |
PLA2-V
A Real Player in Atherogenesis
From the Wihuri Research Institute, Helsinki, Finland.
An important early step in atherosclerosis is binding of apolipoprotein B-100 (apoB-100)–containing lipoproteins (VLDL, IDL, and LDL) to the proteoglycan component of the extracellular matrix of the arterial intima.1,2 When oxidative agents or enzymes attack the proteoglycan-bound lipoproteins, they become oxidatively modified, and when various intimal proteases or lipases hydrolyze them, they become nonoxidatively modified. Whereas oxidation of proteoglycan-bound apoB-100–containing particles triggers their release and subsequent uptake by macrophages, the nonoxidative modifications do the opposite: they enhance the strength of particle binding to proteoglycans.3 In addition, such nonoxidatively modified apoB-100–containing lipoprotein particles tend to aggregate and fuse, which allows progressive extracellular accumulation of lipoprotein lipids, a key phenomenon in atherogenesis. The nonoxidative modifications can also lead to intracellular lipid accumulation and so induce foam cell formation, a hallmark of early atherogenesis.4 Thus, local modification of apoB-100–containing lipoproteins leads to both extra- and intracellular accumulation of lipids in the arterial intima.
See page 600
In general, the nonoxidative modifications are caused by enzymes that are hydrolytic in nature, either proteolytic or lipolytic. Indeed, the arterial intima contains many different types of hydrolytic enzymes capable of lipoprotein modification. Unfortunately, however, it is currently not known which hydrolytic enzymes of the human arterial intima are actually responsible for turning the intimal lipoproteins into atherogenic particles. Among the lipolytic enzymes potentially involved in such atherogenic conversion of lipoproteins are several members of the secretory phospholipase A2 (sPLA2) family. The hydrolytic action of these enzymes on phosphatidylcholine, the major glycerophospholipid in lipoprotein particles, leads to the generation of lysophosphatidylcholine (lysoPC) and a free fatty acid (FFA).
In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Bostrom et al5 have examined in vivo the role of Group V sPLA2 (sPLA2-V) in the context of atherogenesis. The rationale for their studies derives from previous data suggesting a role for the sPLA2 enzymes in atherosclerosis and particularly in lipoprotein modification. An important finding pointing to a role of PLA2 enzymes in the modification of lipoprotein particles locally in the arterial intima comes from compositional analysis of lipoproteins isolated from human atherosclerotic arteries. Thus, such isolated lipoproteins have decreased phosphatidylcholine content,6,7 ie, a change that points to their hydrolysis by a PLA2 enzyme.
Of the 10-member family of sPLA2 enzymes, the effect of Group IIa sPLA2 (sPLA2-IIa) in atherosclerosis has been studied extensively, and accumulating evidence both in vivo and in vitro supports a role for this particular enzyme in atherosclerosis (reviewed by Menschikowski8). However, because sPLA2-IIa has a relatively low hydrolytic activity toward phosphatidylcholines on lipoprotein surfaces, the pathophysiologic role of this enzyme in lipoprotein modification has been questioned.
Another structurally and functionally distinct type of PLA2, the lipoprotein-associated PLA2 (Lp-PLA2), has also been detected in atherosclerotic lesions.9,10 Lp-PLA2 is associated mainly with plasma lipoproteins, particularly with LDL, and is carried into the intima along with LDL particles. In addition, this enzyme can be synthesized and secreted within the plaque by inflammatory cells, such as macrophages, both in early and advanced atherosclerotic lesions.9,10 Lp-PLA2 does not hydrolyze phospholipids on native lipoproteins, but requires oxidation of phospholipids for them to become its substrate.
The action of Lp-PLA2 on oxidatively-modified LDL has been considered to possess both anti- and proinflammatory components.11Thus, by reducing the content of biologically active oxidized phospholipids in minimally modified LDL, Lp-PLA2 blocks the ability of such LDL particles to promote binding of monocytes to endothelial cells in vitro.12 On the other hand, recent experiments have clearly indicated that the hydrolytic products generated by Lp-PLA2 and released from the modified LDL particles, ie, lysophospholipids and oxidized FFAs, elicit proinflammatory responses in various types of cells involved in atherosclerosis (reviewed by MacPhee et al13). Moreover, because increased plasma concentration of Lp-PLA2 is a biomarker of inflammation and denotes increased risk of acute coronary events,13 evidence favoring a proatherogenic role for Lp-PLA2 is accumulating from several lines of studies.
As described above, the two members of the sPLA2 family, sPLA2-IIa and Lp-PLA2, are able to hydrolyze native LDL particles only poorly, or not at all. In contrast, sPLA2-V has been shown to efficiently hydrolyze native LDL.14,15 Most importantly, sPLA2-V is able to hydrolyze lipoproteins in complete serum,15 a finding indicative of the absence of natural inhibitors of the enzyme in serum, and also suggesting their absence in interstitial fluids, such as the intimal fluid, which are derivatives of blood plasma. Thus, the enzyme may also be able to act on lipoproteins in the arterial intima.
Importantly, sPLA2-V has been detected in atherosclerotic lesions, but until now, direct evidence for the contribution of the enzyme in atherogenesis has not been available. In the current issue, Bostrom et al5 in their gain-of-function and loss-of-function studies in mice show that increased expression of sPLA2-V in bone marrow–derived cells increased atherosclerosis, whereas deficiency of PLA2-V in such cells reduced atherosclerosis. The activity of PLA2 in the plasma of the variously treated mice did not change, an observation strongly supporting the idea that increased lipid deposition in mice overexpressing sPLA2-V was indeed attributable to the lipolytic activity of the enzyme within the arterial intima, the actual site of progressive lipoprotein accumulation. As discussed above, the likely substrates for sPLA2 enzymes in the arterial intima are the phosphatidylcholine molecules of the retained apoB-100–containing lipoprotein particles. This assertion is supported by the in vitro findings showing that sPLA2-V can avidly hydrolyze the phosphatidylcholines on lipoprotein surfaces.14,15 Moreover, as the enzyme binds with high affinity to proteoglycans, it has the potential to hydrolyze lipoproteins retained within the proteoglycan meshwork.15 Binding of sPLA2-V to proteoglycans has been shown to actually enhance its lipolytic activity toward lipoproteins,15 so rendering it an even better candidate responsible for lipoprotein hydrolysis in the proteoglycan-rich layer of the arterial intima. Thus, we can conclude that optimal conditions appear to prevail in the arterial intima for this particular member of the family of sPLA2 enzymes.
Hydrolysis of lipoproteins in the arterial intima by sPLA2-V can potentially contribute to atherosclerosis by various mechanisms, and these options are depicted schematically in the Figure. First, phospholipolysis of lipoproteins leads to the generation of relatively high concentrations of FFAs and lysoPCs. Locally, these bioactive lipids may have vasoactive, chemotactic, and proinflammatory effects on arterial smooth muscle cells, macrophages, T cells, and endothelial cells (reviewed by Hurt-Camejo et al16). Second, hydrolysis of the apoB-100–containing lipoproteins (VLDL, IDL, and LDL) by sPLA2 can lead to their aggregation and fusion.17 Once the phosphatidylcholine molecules on the lipoprotein surface are hydrolyzed, the lipoprotein particles become more susceptible to other types of modifications, such as oxidation18 or hydrolysis by secretory sphingomyelinase.19 Third, sPLA2-treatment enhances the binding of LDL to proteoglycans, and this may involve at least two mechanisms. Flood et al20 have shown that sPLA2-treatment induces changes in the conformation of apoB-100, which, again, promote the interaction of LDL with the negatively charged proteoglycans. This finding is consistent with earlier studies showing that the sPLA2-generated small and dense LDL particles bind to proteoglycans more avidly than large and buoyant LDL particles.21 In addition, our laboratory has shown that particle aggregation further enhances the binding strength of the modified LDL particles to proteoglycans.3 This increase can be explained by the fact that LDL aggregates contain many copies of apoB-100, and, being multivalent, have the potential to interact with proteoglycans via more ionic interactions than their nonaggregated, native-sized counterparts. Interestingly, binding of LDL to proteoglycans promotes PLA2-induced aggregation and fusion of LDL particles,22 and an enhanced interaction of sPLA2-V–treated LDL to proteoglycans has been demonstrated by Rosengren et al.15 In terms of atherogenesis, the full repertoire of the above-listed interactions between lipoproteins, sPLA2-V, and intimal proteogycans is likely to contribute to extracellular accumulation of lipoprotein-derived lipids. Finally, modification of LDL by sPLA2-V can also contribute to intracellular lipid accumulation by leading to the formation of macrophage foam cells.14,23 Here, a recent mechanistic insight provides an extra flavor to the story: the increased uptake of sPLA2-V–treated LDL appears to depend on the increased affinity of the modified LDL to the heparan sulfate proteoglycans present on the cell surface.23
|
The work of Bostrom et al5 complements the wealth of in vitro data regarding the proatherogenic role of sPLA2-V and provides the first in vivo support for the local action of sPLA2-V in the arterial intima of an experimental animal. The presence of sPLA2-V in lipid-rich regions of human and mouse atherosclerotic lesions and its potent activity toward lipoproteins, particularly in the presence of proteoglycans, both point to the possibility of this enzyme being a key player in lipoprotein modification during atherogenesis. Indeed, the road ahead for novel discoveries in this important field of scientific exploration of lipolytic pathways in atherogenesis looks quite promising.
 |
Acknowledgments |
|---|
Disclosures
None.
|
Footnotes |
|---|
Correspondence to Petri T. Kovanen, Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland. E-mail petri.kovanen@wri.fi
|
References |
|---|
 Top References |
|---|
- Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995; 15: 551–561.
[Free Full Text] - Williams KJ, Tabas I. The response-to-retention hypothesis of atherogenesis reinforced. Curr Opin Lipidology. 1998; 9: 471–474.[CrossRef][Medline] [Order article via Infotrieve]
- Öörni K, Pentikäinen MO, Ala-Korpela M, Kovanen PT. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J Lipid Res. 2000; 41: 1703–1714.
[Abstract/Free Full Text] - Tabas I. Nonoxidative modifications of lipoproteins in atherogenesis. Annu Rev Nutr. 1999; 19: 123–139.[CrossRef][Medline] [Order article via Infotrieve]
- Bostrom MA, Boyanovsky BB, Jordan CT, Wadsworth MP, Taatjes DJ, de Beer RC, Webb NR Group V secretory phospholipase A2 promotes atherosclerosis: evidence from genetically altered mice. Arterioscler Thromb Vasc Biol. 2007; 27: 600–606.
[Abstract/Free Full Text] - Camejo G, Hurt E, Romano M. Properties of lipoprotein complexes isolated by affinity chromatography from human aorta. Biomed Biochim Acta. 1985; 44: 389–401.[Medline] [Order article via Infotrieve]
- Tailleux A, Torpier G, Caron B, Fruchart J-C, Fievet C. Immunological properties of apoB-containing lipoprotein particles in human atherosclerotic arteries. J Lipid Res. 1993; 34: 719–728.[Abstract]
- Menschikowski M, Hagelgans A, Siegert G. Secretory phospholipase A2 of group IIA: is it an offensive or a defensive player during atherosclerosis and other inflammatory diseases? Prostaglandins Other Lipid Mediat. 2006; 79: 1–33.[CrossRef][Medline] [Order article via Infotrieve]
- Häkkinen T, Luoma JS, Hiltunen MO, MacPhee CH, Milliner KJ, Patel L, Rice SQ, Tew DG, Karkola K, Ylä-Herttuala S. Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 1999; 19: 2909–2917.
[Abstract/Free Full Text] - Kolodgie FD, Burke AP, Skorija KS, Ladich E, Kutys R, Makuria AT, Virmani R. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2006; 26: 2523–2529.
[Abstract/Free Full Text] - Kovanen PT, Pentikäinen MO. Circulating lipoproteins as proinflammatory and anti-inflammatory particles in atherogenesis. Curr Opin Lipidol. 2003; 14: 411–419.[CrossRef][Medline] [Order article via Infotrieve]
- Watson AD, Navab M, Hama SY, Sevanian A, Prescott SM, Stafforini DM, McIntyre TM, Du BN, Fogelman AM, Berliner JA. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest. 1995; 95: 774–782.[Medline] [Order article via Infotrieve]
- MacPhee CH, Nelson J, Zalewski A. Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target. Curr Opin Pharmacol. 2006; 6: 154–161.[CrossRef][Medline] [Order article via Infotrieve]
- Wooton-Kee CR, Boyanovsky BB, Nasser MS, de Villiers WJ, Webb NR. Group V sPLA2 hydrolysis of low-density lipoprotein results in spontaneous particle aggregation and promotes macrophage foam cell formation. Arterioscler Thromb Vasc Biol. 2004; 24: 762–767.
[Abstract/Free Full Text] - Rosengren B, Peilot H, Umaerus M, Jonsson-Rylander AC, Mattsson-Hulten L, Hallberg C, Cronet P, Rodriguez-Lee M, Hurt-Camejo E. Secretory phospholipase A2 Group V: lesion distribution, activation by arterial proteoglycans, and induction in aorta by a western diet. Arterioscler Thromb Vasc Biol. 2006; 26: 1579–1585.[CrossRef][Medline] [Order article via Infotrieve]
- Hurt-Camejo E, Camejo G, Peilot H, Öörni K, Kovanen PT. Phospholipase A2 in vascular disease. Circ Res. 2001; 89: 298–304.
[Abstract/Free Full Text] - Öörni K, Posio P, Ala-Korpela M, Jauhiainen M, Kovanen PT. Sphingomyelinase induces aggregation and fusion of small very low-density lipoprotein and intermediate-density lipoprotein particles and increases their retention to human arterial proteoglycans. Arterioscler Thromb Vasc Biol. 2005; 25: 1678–1683.
[Abstract/Free Full Text] - Sparrow CP, Parthasarathy S, Steinberg D. Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell-mediated oxidative modifiaction. J Lipid Res. 1988; 29: 745–753.[Abstract]
- Schissel SL, Jiang XC, Tweedie-Hardman J, Jeong T-S, Hurt-Camejo E, Najib J, Rapp JH, Williams KJ, Tabas I. Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J Biol Chem. 1998; 273: 2738–2746.
[Abstract/Free Full Text] - Flood C, Gustafsson M, Pitas RE, Arnaboldi L, Walzem RL, Borén J. Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100. Arterioscler Thromb Vasc Biol. 2004; 24: 564–570.
[Abstract/Free Full Text] - Sartipy P, Camejo G, Svensson L, Hurt-Camejo E. Phospholipase A(2) modification of low density lipoprotein forms small high density particles with increased affinity for proteoglycans and glycosaminoglycans. J Biol Chem. 1999; 274: 25913–25920.
[Abstract/Free Full Text] - Hakala JK, Öörni K, Ala-Korpela M, Kovanen PT. Lipolytic modification of LDL by phospholipase A2 induces particle aggregation in the absence and fusion in the presence of heparin. Arterioscler Thromb Vasc Biol. 1999; 19: 1276–1283.
[Abstract/Free Full Text] - Boyanovsky BB, Van der Westhuyzen DR, Webb NR. Group V secretory phospholipase A2-modified low density lipoprotein promotes foam cell formation by a SR-A- and CD36-independent process that involves cellular proteoglycans. J Biol Chem. 2005; 280: 32746–32752.
[Abstract/Free Full Text]
Related Article:
- Group V Secretory Phospholipase A2 Promotes Atherosclerosis: Evidence From Genetically Altered Mice
- Meredith A. Bostrom, Boris B. Boyanovsky, Craig T. Jordan, Marilyn P. Wadsworth, Douglas J. Taatjes, Frederick C. de Beer, and Nancy R. Webb
Arterioscler. Thromb. Vasc. Biol. 2007 27: 600-606.[Abstract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  T. Parasassi, M. De Spirito, G. Mei, R. Brunelli, G. Greco, L. Lenzi, G. Maulucci, E. Nicolai, M. Papi, G. Arcovito, et al. Low density lipoprotein misfolding and amyloidogenesis FASEB J, July 1, 2008; 22(7): 2350 - 2356. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||