doi: 10.1161/01.ATV.0000227561.89488.9a
© 2006 American Heart Association, Inc.
Editorials |
Inflammation and Atherosclerosis
Group IIa and Group V sPLA2 Are Not Redundant
From the Department of Internal Medicine and Cardiovascular Research Center, University of Kentucky, Lexington.
Correspondence to Frederick C. de Beer, Department of Internal Medicine, University of Kentucky Medical Center, 740 S Limestone, Room J-525, Lexington, KY 40536-0284. E-mail fcdebe1{at}uky.edu
The secretory phospholipase A2 (sPLA2) family hydrolyzes glycerophospholipids at the sn-2 position to generate lysophospholipids and free fatty acids. Ten members have been described in mammals. These enzymes must be clearly distinguished from the intracellular phospholipase A2s that are involved in intracellular signaling. They are also distinct from lipoprotein-associated phospholipase A2 (Lp-PLA2), which has been shown to be bound predominantly to LDL particles in human plasma, and hydrolyzes oxidized LDL to generate lysophosphatidylcholine and oxidized nonesterified fatty acids.1 Group IIa sPLA2, which was originally isolated from rheumatoid arthritis fluids, is considered to be the prototypic inflammatory sPLA2. Its expression is markedly elevated in many cell types in response to proinflammatory stimuli. The concentration of Group IIa sPLA2 in sera or exudating fluids correlates well with the severity of inflammatory disease. In humans, Group IIa and Group V sPLA2 are tightly linked on chromosome 1 and their gene regulation and functions have largely been viewed as overlapping. Indeed, cross-reactivity of antibodies and molecular probes for these related enzymes has led to confusion in older literature. The study by Rosengren et al, reported in this issue, provides new insights into the expression and functional activity of Group IIa and Group V sPLA2 in the context of atherosclerosis.2
See page 1579
A role for sPLA2s in atherogenic processes has been suggested by epidemiological studies showing that in humans, serum concentrations of Group IIa sPLA2 is an independent risk factor for coronary artery disease and a predictor of cardiovascular events.3,4 However, because it is well recognized that this enzyme is highly induced in a number of tissues during inflammation, there was uncertainty as to whether this association merely reflected the fact that Group IIa sPLA2 is a marker for inflammation. Whether Group V sPLA2 is an acute phase protein that appears in the plasma during inflammation is less certain. New evidence provided by Rosengren et al2 that Group V sPLA2, unlike Group IIa, is not induced in mice treated with lipopolysaccharide (LPS) is consistent with other findings in humans indicating that sera from patients experiencing inflammatory diseases contain Group IIa sPLA2, and not Group V sPLA2.5 It seems reasonable to propose that the major contribution of Group V sPLA2 to the pathogenesis of atherosclerosis would be effected at the level of the vessel wall.
The finding in 1999 that transgenic expression of human Group IIa sPLA2 in C57BL/6 mice (this strain lacks the expression of endogenous Group IIa sPLA2) leads to spontaneous atherosclerotic lipid deposition even in the absence of dyslipidemia provided compelling evidence that sPLA2 may play a causal role in atherosclerosis and is not just a marker for the disease.6 Subsequent studies showing that macrophage expression of human Group IIa sPLA2 accelerates atherosclerosis in mice highlighted the possibility that the mechanism of the pathogenic effect of sPLA2 may be located within the vessel wall, independent of systemic effects.7 Recent studies, including the accompanying article,2 establish that at least 3 different members of the sPLA2 family are present in atherosclerotic lesions (Group IIA, Group V, and Group X sPLA2). This suggests the intriguing possibility that multiple enzymes may contribute locally to atherosclerotic processes, and raises the question: Are these enzymes redundant, or do they provide separate functions?
Rosengren et al2 report that Group V sPLA2, but not Group IIa sPLA2, hydrolyzes lipoprotein phospholipids in the presence of complete serum. This is consistent with earlier reports indicating that Group V sPLA2 is more potent in hydrolyzing HDL and LDL compared with Group IIa sPLA2.8,9 However, despite this convincing in vitro data, the large body of evidence pointing to the importance of Group IIa sPLA2 in modulating HDL metabolism in vivo should not be ignored. When induced during inflammation, this isozyme associates selectively with HDL and appears to modify the HDL particle. Transgenic mice expressing human Group IIa sPLA2 have lower plasma concentrations of HDL cholesterol and apoA-I compared with normal mice, and HDL particles in the transgenic mice are markedly smaller and relatively phospholipid depleted compared with normal mouse HDL.6 Furthermore, HDL from transgenic mice is markedly depleted of paraoxonase activity, an enzyme that is believed to be partly responsible for the protective effects of HDL.6 The decreased plasma HDL levels in Group IIa sPLA2 transgenic mice appears to be attributed to enhanced HDL catabolism, a phenomenon which is associated with altered tissue uptake of HDL cholesteryl ester and apoA-I.10,11 The relevance of these findings in mice to the human condition seems likely, given the markedly reduced HDL levels in rheumatoid arthritis patients, who have increased plasma Group IIa sPLA2 and accelerated atherosclerosis.
The significance of Group IIa or Group V sPLA2 hydrolysis on HDL function in the vessel wall is not clear. On the one hand, hydrolysis by sPLA2 results in a significant decrease in the capacity of HDL to mediate cellular cholesterol efflux from lipid-loaded macrophages.9 On the other hand, phospholipid depletion by sPLA2 has a major impact on HDL remodeling by cholesteryl ester transfer protein (CETP). Compared with remodeling by CETP alone, the combined action of sPLA2 and CETP enhances the generation of pre-beta migrating, lipid-free/lipid-poor apoA-I,12 the preferred substrate for ABCA1-dependent cellular cholesterol efflux. This effect on HDL remodeling is intriguing and raises the possibility that during inflammation, sPLA2s may fundamentally alter the ratio between HDL-bound and free apolipoproteins. If this is the case, this scenario can be envisaged to promote both the effluxing capacity and catabolism of HDL.
Accumulating evidence suggests that LDLs hydrolyzed by sPLA2 acquire proatherogenic properties. Rosengren et al demonstrate for the first time that Group V sPLA2 activity toward LDL is significantly enhanced in the presence of proteoglycans.2 Thus, extracellular matrix (ECM) proteoglycans play an active role in lipid accumulation in the vessel wall by not only mediating the retention of LDL particles, but by also modulating the activity of LDL hydrolytic enzymes. Interestingly, recent data suggests that hydrolysis by Group V sPLA2 promotes the interaction of LDL particles with cell-surface proteoglycans, and thereby promotes their uptake by macrophages.13 Thus, in regions where LDL is being accumulated, the colocalization of LDL, proteoglycans, and Group V sPLA2 leads to a self-perpetuating cascade of events that culminates in atherosclerosis.
Are Group IIa and Group V sPLA2 redundant with respect to atherogenesis? In vivo data suggests that the acute phase Group IIa sPLA2 plays the predominant, if not exclusive, role in modulating systemic lipoprotein metabolism, despite its relatively weak ability to hydrolyze LDL and HDL in vitro. Whereas Group IIa sPLA2 is induced by proinflammatory cytokines, novel data presented by Rosengren et al suggest that Group V sPLA2 may be upregulated by bioactive lipids.2 The presence of Group V sPLA2 in lipid-rich regions of human and mouse atherosclerotic lesions, its potent activity toward LDL, and its activation by proteoglycans, all point to this enzyme as an important player in the generation of proatherogenic LDL. Clearly, the enzymes investigated by Rosengren et al profoundly influence lipoprotein structure. The functional and pathogenetic implications, particularly during inflammation, merits further study.
 |
Acknowledgments |
|---|
Disclosure(s)
None.
|
References |
|---|
 Top References |
|---|
1. 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]
2. 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]
3. Kugiyama K, Ota Y, Takazoe K, Moriyama Y, Kawano H, Miyao Y, Sakamoto T, Soejima H, Ogawa H, Doi H, Sugiyama S, Yasue H. Circulating levels of secretory type II phospholipase A(2) predict coronary events in patients with coronary artery disease. Circulation. 1999; 100: 1280–1284.
4. Boekholdt SM, Keller TT, Wareham NJ, Luben R, Bingham SA, Day NE, Sandhu MS, Jukema JW, Kastelein JJ, Hack CE, Khaw KT. Serum levels of type II secretory phospholipase A2 and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. Arterioscler Thromb Vasc Biol. 2005; 25: 839–846.
5. Aarsman AJ, Neys FW, van der Helm HA, Kuypers FA, van den Bosch H. Sera of patients suffering from inflammatory diseases contain group IIA but not group V phospholipase A(2). Biochim Biophys Acta. 2000; 1502: 257–263.[Medline] [Order article via Infotrieve]
6. Ivandic B, Castellani LW, Wang X-P, Qiao J-H, Mehrabian M, Navab M, Fogelman AM, Grass DS, Swanson ME, de Beer MC, de Beer F, Lusis AJ. Role of group II secretory phospholipase A2 in atherosclerosis 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase A2. Arterioscler Thromb Vasc Biol. 1999; 19: 1284–1290.
7. Webb NR, Bostrom MA, Szilvassy SJ, van der Westhuyzen DR, Daugherty A, de Beer FC. Macrophage-expressed Group IIA sPLA2 increases atherosclerotic lesion formation in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2003; 23: 263–268.
8. Gesquiere L, Cho W, Subbaiah PV. Role of group IIa and group V secretory phospholipases A(2) in the metabolism of lipoproteins. Substrate specificities of the enzymes and the regulation of their activities by sphingomyelin. Biochemistry. 2002; 41: 4911–4920.[CrossRef][Medline] [Order article via Infotrieve]
9. Ishimoto Y, Yamada K, Yamamoto S, Ono T, Notoya M, Hanasaki K. Group V and X secretory phospholipase A(2)s-induced modification of high-density lipoprotein linked to the reduction of its antiatherogenic functions. Biochim Biophys Acta. 2003; 1642: 129–138.[Medline] [Order article via Infotrieve]
10. de Beer FC, Connell PM, Yu J, de Beer MC, Webb NR, van der Westhuyzen DR. HDL modification by secretory phospholipase A2 promotes SR-BI interaction and accelerates HDL metabolism. J Lipid Res. 2000; 41: 1849–1857.
11. Tietge UJF, Maugeais C, Cain W, Grass D, Glick JM, de Beer FC, Rader DJ. Overexpression of secretory phospholipase A2 causes rapid catabolism and altered tissue uptake of high density lipoprotein cholesteryl ester and apolipoprotein A-I. J Biol Chem. 2000; 275: 10077–10084.
12. Rye KA, Duong MN. Influence of phospholipid depletion on the size, structure, and remodeling of reconstituted high density lipoproteins. J Lipid Res. 2000; 41: 1640–1650.
13. 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.
Related Article:
Arterioscler Thromb Vasc Biol 2006 26: 1579-1585.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||