Document Detail

The secretory phospholipase A2 group IIA: a missing link between inflammation, activated renin-angiotensin system, and atherogenesis?
Jump to Full Text
MedLine Citation:
PMID:  18827909     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Inflammation, lipid peroxidation and chronic activation of the renin-angiotensin system (RAS) are hallmarks of the development of atherosclerosis. Recent studies have suggested the involvement of the pro-inflammatory secretory phospholipase A(2) (sPLA(2))-IIA in atherogenesis. This enzyme is produced by different cell types through stimulation by pro-inflammatory cytokines. It is detectable in the intima and in media smooth muscle cells, not only in atherosclerotic lesions but also in the very early stages of atherogenesis. sPLA(2)-IIA can hydrolyse the phospholipid monolayers of low density lipoproteins (LDL). Such modified LDL show increased affinity to proteoglycans. The modified particles have a greater tendency to aggregate and an enhanced ability to insert cholesterol into cells. This modification may promote macrophage LDL uptake leading to the formation of foam cells. Furthermore, sPLA(2)-IIA is not only a mediator for localized inflammation but may be also used as an independent predictor of adverse outcomes in patients with stable coronary artery disease or acute coronary syndromes. An interaction between activated RAS and phospholipases has been indicated by observations showing that inhibitors of sPLA(2) decrease angiotensin (Ang) II-induced macrophage lipid peroxidation. Meanwhile, various interactions between Ang II and oxLDL have been demonstrated suggesting a central role of sPLA(2)-IIA in these processes and offering a possible target for treatment. The role of sPLA(2)-IIA in the perpetuation of atherosclerosis appears to be the missing link between inflammation, activated RAS and lipid peroxidation.
Authors:
Dimitar Divchev; Bernhard Schieffer
Related Documents :
18497309 - Lentiviral transduction of apoai into hematopoietic progenitor cells and macrophages: a...
11208689 - An hmg-coa reductase inhibitor, cerivastatin, suppresses growth of macrophages expressi...
16733369 - Different vascular smooth muscle cell apoptosis in the human internal mammary artery an...
18091649 - Antibodies to oxidized low density lipoprotein: epidemiological studies and potential c...
2697759 - The cellular biology of angiotensin: paracrine, autocrine and intracrine actions in car...
15761189 - Connective tissue growth factor is overexpressed in complicated atherosclerotic plaques...
17349619 - Protective effects of salidroside on hydrogen peroxide-induced apoptosis in sh-sy5y hum...
8923129 - Prospects for the immunological control of ruminant gastrointestinal nematodes: natural...
12573279 - Cytochrome c-induced cytosolic nicotinamide adenine dinucleotide oxidation, mitochondri...
Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Vascular health and risk management     Volume:  4     ISSN:  1176-6344     ISO Abbreviation:  Vasc Health Risk Manag     Publication Date:  2008  
Date Detail:
Created Date:  2008-10-01     Completed Date:  2008-10-28     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  101273479     Medline TA:  Vasc Health Risk Manag     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  597-604     Citation Subset:  IM    
Affiliation:
Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Germany.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Acute Coronary Syndrome / blood,  physiopathology
Atherosclerosis / physiopathology*
Coronary Artery Disease / blood,  physiopathology
Group II Phospholipases A2 / blood,  physiology*
Humans
Inflammation / physiopathology*
Lipid Peroxidation / physiology
Macrophages / metabolism
Prognosis
Receptor, Angiotensin, Type 1 / physiology
Renin-Angiotensin System / physiology*
Chemical
Reg. No./Substance:
0/Receptor, Angiotensin, Type 1; EC 3.1.1.4/Group II Phospholipases A2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Vasc Health Risk Manag
Journal ID (publisher-id): Vascular Health and Risk Management
ISSN: 1176-6344
ISSN: 1178-2048
Publisher: Dove Medical Press
Article Information
Download PDF
? 2008 Divchev and Schieffer, publisher and licensee Dove Medical Press Ltd.
Print publication date: Month: 6 Year: 2008
Electronic publication date: Month: 6 Year: 2008
Volume: 4 Issue: 3
First Page: 597 Last Page: 604
ID: 2515419
PubMed Id: 18827909

The secretory phospholipase A2 group IIA: a missing link between inflammation, activated renin-angiotensin system, and atherogenesis?
Dimitar Divchev
Bernhard Schieffer
Department of Cardiology and Angiology, Medizinische HochschuleHannover, Germany
Correspondence: Correspondence: Bernhard Schieffer Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1 30625 Hannover, Germany Tel +49 511 532 2129 Fax +49 511 532 3357 Email schieffer.bernhard@mh-hannover.de

Introduction

Atherosclerosis with its associated cardiovascular events, myocardial infarction (MI), sudden cardiac death or stroke, is one of the leading causes of death in the western countries (Ross 1999). Inflammation and lipid peroxidation, as well as chronic activation of the renin-angiotensin system (RAS), are hallmarks of atherogenesis. Activated RAS, inflammatory processes and lipid peroxidaton products contribute to the initiation, progression and rupture of atherosclerotic plaques (Neaton et al 1992; Lowe et al 1998; Thomas et al 2002). Therefore reducing pro-inflammatory mediators, and inhibiting the modulation of their releasing pathways, may be important both for the stability of atherosclerotic lesions and the perpetuation of atherosclerotic plaques (Taniguchi et al 2005).

In addition to this link, more direct interactions have been suggested between a chronically activated RAS, and elevated pro-inflammatory cytokines and lipoproteins, which may also promote atherogenesis (Nickenig et al 2000). An increasing amount of evidence indicates that secretory phospholipase A2 (sPLA2) enzymes present in the vessel wall have localized effects that promote these processes (Kovanen et al 2000; Hurt-Camejo et al 2001; Niessen et al 2003; Tietge et al 2005; Menschikowski et al 2006). Three members (group IIA, group V and group X) of the various sPLA2 isozymes have been detected in murine or human atherosclerotic lesions (Murakami et al 2004; Rosengreen et al 2004; Wooton-Kee et al 2004); expression and localization of secretory phospholipase A2 group IIA (sPLA2-IIA) in human atherosclerotic tissue have been the best documented until now (Six et al 2000; Kudo et al 2002; Jaross et al 2002). In this context, recent investigations have suggested the involvement of sPLA2-IIA as part of a systemic and localized acute-phase-reaction in the development of atherosclerosis, not only as a specific marker of inflammation but probably as a central link between activated RAS and lipid peroxidation (Keidar et al 1997; Hayek et al 2000; Luchtefeld et al 2006; Divchev et al pers comm).

This study explains the importance of sPLA2-IIA as a key enzyme of inflammation-based atherosclerotic development, and a prognostic marker of cardiovascular events, based on current literature and the experimental findings of our group.


What are phospholipases (in general sPLA2s) good for?

Phospholipases are enzymes that play a crucial role in the metabolism of phospholipids. Various groups and a remarkable number of subgroups have been identified, but specific functions for only some of these phospholipases have been established in humans. Their classification is related to the site of action on the phospholipid molecules. In this context, phospholipases may act as acylhydrolases (PLAs and PLB), lysophospholipases or phosphodiesterases (PLC and PLD) (Six et al 2000; Kudo et al 2002). For example, phospholipases A2 (PLA2s) catalyze the sn-2 ester bonds of glycerophospholipids and, more importantly, appear to be the most influential subfamily in pro-inflammatory processes and thereby in inflammation-initiated diseases.

This subfamily can be characterized as a group of calcium-dependent lipolytic enzymes with a preserved calcium-binding loop and a His-Asp diad at the catalytic site. More then 13 groups and up to 20 different subgroups have been described so far (Six et al 2000; Kudo et al 2002; Jaross et al 2002). Nonsecretory PLA2s include the Ca2+-sensitive arachidonoyl-selective 85-kDa group IV? cytosolic PLA2 (cPLA2?) (Leslie 1997; Bonventre 1999), paralogs of this enzyme (Pickard et al 1999), and several Ca2+-independent PLA2s (iPLA2s) (Balsinde et al 1997).

Many cell types can secrete sPLA2s, especially sPLA2-IIA such as mesangial cells (Pfeilschifter et al 1989; Schalkwijk et al 1991), vascular smooth muscle (Nakano et al 1990; Kurihara et al 1991), endothelial cells (Murakami et al 1993), platelets (Hayakawa et al 1988), mast cells (Foneth et al 1994; Reddy et al 1996), neutrophils (Wright et al 1990), macrophages (Hidi et al 1993; Brabour et al 1993; Vial et al 1995), and hepatic cells (Crowl et al 1991).

Several pro-inflammatory stimuli may lead to secretion of diverse enzymes including phospholipases as part of a host defense mechanism. Such stimuli could be microbial pathogens as well as chemical irritants, allergens or physical stress factors. CPLA2? as well as the sPLA2s have been involved in various physiological and pathological functions such as release of pro-inflammatory mediators, cell proliferation, ischemic injury, inflammatory and allergic disease, lipid modification, cancer, and antibacterial defense (Bonventre 1999; Valentin et al 1999; Sapirstein et al 2000; Granata et al 2003). The presence of sPLA2-IIA activity in tears or seminal plasma, which may come into contact with bacterial pathogens, also suggests primary antibacterial properties of these enzymes. In this sense, sPLA2-IIA is able to destroy the membranes of Gram-positive bacteria. Interestingly, in Gram-negative bacteria sPLA2-IIA cannot directly attack the phospholipids of the intact cell membranes, but needs the cooperative action of neutrophils which produce bactericidal permeability-increasing protein (BPI) to support this function (Wright et al 1990; Laine et al 1999). Phospholipases could therefore act in the frame of combined inflammation associated humoral and cellular responses.

SPLA2s do not exhibit acyl chain specificity, whereas a preferential effect on arachidonic acid (AA)-containing membrane phospholipids, compared with those containing other fatty acids, could be demonstrated for cPLA2?. The cPLA2?, group IIA, and group V PLA2s are the primary PLA2s responsible for producing AA and its metabolites in endothelial, fibroblastic mast and macrophage cell lines (Balboa et al 1996; Reddy et al 1997; Pruzanski et al 1998). A profound cross-talk between cytosolic phospholipase A2 (cPLA2) and sPLA2-IIA with regard to free radical release has been confirmed by some investigations (Han et al 2003). Immunohistochemistry studies have further demonstrated the presence of group IIA, group V and group X secretory phospholipase A2 in murine and human atherosclerotic lesions (Murakami et al 2004; Rosengren et al 2004; Wooton-Kee et al 2004; Webb 2005).

On the other hand, it could be shown that there are changes in serum cholesterol levels with decreased concentrations of high density (HDL) and low density lipoproteins (LDL) in patients suffering from generalized infectious diseases such as sepsis. Moreover, a frequent finding in patients with persisting infections, metastatic tumors or chronic inflammatory diseases is hypocholesterolemia (Green et al 1991; Vadas et al 1993). The serum concentration of sPLA2-IIA, especially the activity of the enzyme, is markedly increased in these diseases, acting as an acute-phase-reactant (de Beer et al 1997; Ivandic et al 1999; Menschikowski et al 2000).

In acute or chronic inflammatory states, serum levels of pro-inflammatory cytokines, such as interleukin (IL)-1?, IL-6, tumor necrosis factor (TNF)-?, and interferon (IFN)-? are also increased and may induce sPLA2-IIA (Peilot et al 2000; Menschikowski et al 2000; Antonio et al 2002). These pro-inflammatory cytokines can also be released at an increased rate by the liver and locally by other cells especially within the atherosclerotic plaque. Such increased PLA2-activity in serum is thought to lead to a more efficient clearance of lipoproteins mainly through the liver, thereby resulting in hypocholesterolemia (de Beer et al 1997; Ivandic et al 1999; Menschikowski et al 2000; Jaross et al 2002).

Therefore, early evidence suggested the existence of a central link between systemic as well as local inflammatory processes and lipid metabolism, and that this link could be sPLA2-IIA.


The secretory phospholipase A2, group IIA role in atherogenesis

The key role played by sPLA2-IIA in the development of atherosclerosis, not merely as a mediator for localized inflammation, has been indicated by a number of recent in-vitro and in-vivo studies as follows. The enzyme seems to play an important role as an integral modulator at several stages of atherogenesis.

In the arterial wall, sPLA2, especially sPLA2-IIA, may exert proatherogenic effects in multiple steps (Hurt-Camejo et al 2001). The isoenzyme sPLA2-IIA is located mainly in vascular smooth muscle cells of normal human arteries (Romano et al 1998; Sartipy et al 1998). In contrast, in atherosclerotic plaques the enzyme is detectable within the lipid cores, in macrophage-rich regions and in the extracellular matrices of the affected intima. Furthermore, sPLA2-IIA has a close spatial relationship to collagen fibres (Romano et al 1998). As mentioned above, the expression of sPLA2-IIA in these cells is assumed to be up-regulated in vitro by several cytokines present in human atherosclerotic lesions, including IL-1?, TNF-? and IFN (Menschikowski et al 2000; Peilot et al 2000; Antonio et al 2002).

One of the first important features in atherogenesis is the retention of LDL particles in the subendothelial space. The modification of LDL mediated by sPLA2-IIA can change the structural organisation of the LDL particle leading to more pronounced lipid accumulation in the vessel wall. Such sPLA2-IIA modified LDL are characterized through an increased affinity for proteoglycans.

As a result of the hydrolytic activity, sPLA2-IIA releases free fatty acids and lyso-phosphatidylcholine(PC) (Yuan et al 1995; Arbibe et al 1998; Fourcade et al 1998; Hurt-Camejo et al 2001; Hurt-Camejo et al 2001). This action may affect the functions and properties of vascular endothelial and smooth muscle cells, and of macrophages, at sites of LDL accumulation (Sparrow et al 1988; Leitinger et al 1999). It should be noted that sPLA2-IIA prefers phosphatidic acid (PA) as substrate over other phospholipids found in plasma membranes including phosphatidylserine (PS), phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Sintko and colleagues reported the following order of substrate preference: PA > PE approximately PS > PC (Snitko et al 1997).

The ability of sPLA2-IIA to hydrolyze PC seems to be weak, but several conditions may amplify that function. sPLA2-IIA acts on oxidized (ox-)LDL more efficiently by transforming LDL to a more atherogenic form. This action is based on the fact that oxidative modification of phospholipids increases their sPLA2-IIA susceptibility (Eckey et al 1997). Furthermore, the closed spatial contact of sPLA2-IIA with matrix proteoglycans (in general decorin, biglycan and versican) may increase the hydrolytic activity of sPLA2-IIA toward PC in LDL (Sartipy et al 2000).

Moreover, sPLA2-IIA modified proteoglycan-bound lipoproteins show a greater tendency to aggregation and fusion. The result is a progressive deposition of lipids within the extracellular matrices of the arterial intima (Hakala et al 2001). In addition to enhancing the retention of LDL particles in the vessel wall, there is also evidence that sPLA2 modification may promote macrophage LDL uptake, leading to foam cell formation (Heinecke et al 1991; Aviram et al 1992).

It should be noted that other sPLA isoenzymes detectable in circulation and human atherosclerotic lesions, especially of group V and group X, have more potent actions on lipoproteins compared with sPLA2-IIA (Bezzine et al 2000; Hanasaki et al 2002; Gesquiere et al 2002). Obviously, the sole potency of sPLA2-IIA in hydrolyzing the primary substrates phosphatidylethanolamine and phosphatidylserine may not be the only important feature in atherosclerotic plaque perpetuation, especially in transforming LDL into more atherogenic forms. Interestingly, sPLA2-V has a preferential action in hydrolysis of HDL compared with LDL, as reviewed by Murakami and Kudo (2003). Similar to sPLA2-V, sPLA2-X definitely shows more pronounced PC-hydrolysing activity. On the other hand, sPLA2-X modified LDL particles have a lower tendency to aggregate (Hanasaki et al 2002; Murakami et al 2003). Nevertheless, we can suppose that sPLA2 isoenzymes may act synergistically under certain conditions (Shoda et al 1999).

Together, HDL and apolipoprotein A-I(apoA-I) are positive prognostic factors in preventing perpetuation of arteriosclerotic plaque formation; there is increasing evidence that sPLA2-IIA may transform these particles to pro-atherogenic and pro-inflammatory reactants. As shown by de Beer and colleagues, sPLA2-IIA dependent hydrolysis of HDL results in a more efficient scavenger receptor class B type I cholesteryl ester uptake, leading to an accelerated HDL catabolism in the kidney during inflammatory states (deBeer et al 2000). Moreover, HDL- and ApoA-I-catabolism as well as HDL-cholesteryl ester tissue uptake were significantly enhanced under conditions of sPLA2-IIA overexpression even in the absence of inflammatory preconditions (Tietge et al 2000).

The above mentioned effects promoted by sPLA2-IIA ? in general the release of AA ? are primarily based on increased enzyme activity. However, the noteworthy non-enzymatic properties of sPLA2-IIA can also contribute to atherogenesis. In this way, catalytic inactive sPLA2-IIA was shown to promote COX-2 expression in mast cells (Tada et al 1998). Further effects may be mediated by the sPLA2 M-type receptor on smooth muscle cells independent of enzyme activity (Silliman et al 2002) and by activating signaling pathways such as ERK (Han et al 2003) MAP kinases or protein kinase C (Hernandez et al 1998). Further research is needed to make clear whether these effects are present in atherosclerotic lesions, and how far they may contribute to atherogenesis.


sPLA2-IIA as a prognostic marker in coronary artery disease

In a similar way to chronic inflammatory diseases, plasma levels of sPLA2-IIA were shown to be elevated in patients with coronary artery disease (CAD) and to predict coronary events in asymptomatic patients or patients with stable angina (Kugiyama et al 1999). Moreover, increased plasma levels of sPLA2 in stable patients undergoing percutaneous coronary angioplasty (PCI) also provide independent prognostic information over other classic cardiovascular risk factors and clinical covariables (Liu et al 2003). The prognostic value of sPLA2-IIA in patients with acute coronary syndromes (ACS) was first described in a study of patients with unstable angina by Kugiyama and colleagues (2000). Increased plasma levels of sPLA2-IIA predicted recurrent coronary events, mainly revascularization procedures, independently of other established risk factors (Kugiyama et al 2000). Mallat and colleagues (2007) also evaluated the prognostic importance of plasma sPLA2-IIA levels and enzyme activity across the entire spectrum of ACS by recruiting patients from the Global Registry of Acute Coronary Events (GRACE). In this impressive study, they showed that plasma sPLA2 activity, in contrast to CRP or IL-18, was a major independent predictor of death and new or recurrent myocardial infarction (MI) in patients with ACS. Interestingly, total sPLA2-activity had a better prognostic value than the sPLA2-IIA antigen level.

However the study?s most important finding was the fact that a single determination of sPLA2-activity, obtained during the two days after the onset of ischemic symptoms, provides powerful prognostic information in patients with ACS. The association between sPLA2 activity and the risk of subsequent death or MI was independent of the other known predictors of major adverse outcomes in patients with ACS, including the presence or absence of a history of MI or signs of heart failure at admission (Mallat et al 2005).

Additional evidence to confirm the importance of catalytic activity, as well as an elevated sPLA2-IIA antigen level, was gathered by Korotaeva and colleagues (2005). They demonstrated that sPLA2-IIA is involved in the development of restenosis after PTCA in human coronary arteries and in the generation of atherogenic LDL (Korotaeva et al 2005).

Interestingly, sPLA2-IIA also seems to play an important role in predicting risk for coronary artery disease and adverse coronary events in healthy subjects, especially when combined with other pro-inflammatory risk factors like CRP (Boekholdt et al 2005; Mallat et al 2007).

Thus sPLA2-IIA can be shown to be not only a mediator for localized inflammation but also a powerful independent predictor of adverse outcomes in patients with stable CAD, or in acute coronary syndromes.


Angiotensin, LDL-peroxidation, and atherogenesis

Early evidence of a potential role for angiotensin (Ang) II in LDL oxidation was gathered by Keidar (1998) who reported that the LDL of hypertensive patients was more responsive to oxidative modification than the LDL of normotensive subjects. Meanwhile, various interactions between Ang II and oxLDL have been demonstrated especially by the Keidar group. For example, Ang-II injection into apolipoprotein E-deficient (E0) mice led to increased cellular oxLDL uptake by their peritoneal macrophages (MPMs) via proteoglycan macrophage stimulation pathway, a process mediated by Il-6 (Keidar et al 1995, 2001). In human coronary endothelial cells, Ang-II enhanced the oxLDL-uptake by up-regulating the lectin-like receptor for oxLDL (LOX-1). This effect could be blocked by the angiotensin receptor blockers (ARBs) Losartan and Candesartan (Mehta et al 2001, 2002). Ang-II increased the cellular lipid peroxidation of MPMs by 50%?100%. Moreover, Ang-II enhanced scavenger receptor affinity to oxLDL on macrophages (Keidar 1998).

The effects of Ang-II are predominantly mediated via activation of the AT1-receptor which is coupled through guanine nucleotide binding proteins (G-proteins), adenylate cyclase and cyclic adenosine monophosphate (cAMP) as second messenger, as well as phospholipases A2, C and D and their products, arachidonic acid (AA), inositol triphosphate (IP3), or diacylglycerol (DG).

The mechanism of Ang-II-mediated cellular lipid peroxidation involved Ang-II binding to its cellular receptor underlined by the fact that preincubation of the cells with the Ang-II antagonist, saralasin, completely inhibited this effect. Inhibitors of phospholipase A2, C and D also substantially reduced Ang-II-induced macrophage lipid peroxidation (Keidar et al 1995).

Interestingly, AT1-receptor blockade with Losartan inhibited LDL oxidation and macrophage cholesterol biosynthesis (Keidar et al 1999), and attenuated atherosclerosis in E0 mice (Keidar et al 1997). In a trial by Hayek and colleagues (2000), losartan therapy for a period of 4 weeks did not significantly affect the degradation of native LDL monocyte-derived macrophages (HMDM) derived from patients. However, Losartan therapy significantly reduced HMDM uptake of oxLDL as shown by a 78% reduction in oxLDL cell-association and a 21% reduction in oxLDL degradation (Hayek et al 2000), a finding which has been also confirmed for other ARBs (Metha et al 2001, 2002).

All these findings suggested an integral link between angiotensin II (Ang-II) and its receptor mediated effects, and activation of pro-inflammatory and pro-atherogenic pathways which could further promote lipid peroxidation.


sPLA2-IIA, the possible link between activated RAS, inflammation, and lipidperoxidation: a target for treatment?

As mentioned above, angiotensin II type 1 (AT1)-receptor blockade may reduce LDL-modification and atherosclerotic plaque formation in animal models of atherosclerosis. Furthermore, Cassis and colleagues (2007) demonstrated that AT1-mediated atherogenesis is dependent on AT1 expression in the vessel wall, and that the presence of this receptor in resident tissues is required to initiate AngII-induced atherosclerosis. Because of increasing evidence for involvement of sPLA2-IIA in modifying LDL, our group assessed whether ANG II, via its AT1-receptor, enhances sPLA2-IIA-dependent lipid peroxidation in vitro and in patients with CAD. Therefore, rat aortic smooth muscle cells were stimulated with ANG II. This stimulation resulted in enhanced sPLA2-IIA protein expression and sPLA2-IIA activity. LDL-peroxidation was consequently enhanced by ANG II. Interestingly, all these effects could be reduced by AT1-receptor blockade with losartan. Furthermore, ANG II-induced sPLA2 activity and LDL-peroxidation were prevented by the sPLA2-IIA activity inhibitor LY311727 (Luchtefeld et al 2006).

These findings suggested that sPLA2-IIA activation could be the supposed link between activated RAS and lipidperoxidation, and that ANG II may elicit pro-atherosclerotic effects via sPLA2-IIA-dependent LDL-modification.

In order to evaluate potential clinical implications of these findings, a small number of patients with angiographically documented CAD were treated with the AT1-receptor blocker irbesartan (300 mg/d) for 12 weeks. Blood samples were obtained from patients pre- and post-treatment and from healthy volunteers. SPLA2-IIA serum level and activity, circulating antibodies against oxidized LDL (oxLDL) and oxLDL, were determined in patients and found to be significantly increased compared to healthy volunteers. Irbesartan therapy reduced these markers of inflammation, whereas total cholesterol, HDL- and LDL-fractions remained unchanged (Luchtefeld et al 2006).

Based on these findings we investigated further the potential effect of a combined treatment with pravastatin and irbesartan on oxLDL and sPLA2-IIA in a group of patients with CAD. We postulated that the addition of an AT1-receptor antagonist to the standard secondary prevention therapy with a statin might exert additional effects on LDL oxidation and sPLA2-IIA. We demonstrated that both treatment regimens comparably influenced LDL-cholesterol levels. However, sPLA2 activity was reduced only in patients treated with the adjunction of pravastatin and irbesartan. Consequently, only the combined treatment resulted in a significant reduction of ox-LDL levels independent of changes in LDL cholesterol (Divchev et al pers comm).

All these findings suggest a possible role for AT1-receptor blockade in reducing LDL-peroxidation. Whether these effects can reduce the perpetuation of atherosclerosis and especially adverse cardiovascular events in patient with CAD remains to be elucidated in further studies.


Conclusion

In conclusion, secretory phospholipases A2 (in general sPLA2-IIA) were shown to play an important role in atherogenesis. Furthermore, the activity of sPLA2-IIA is a powerful independent predictor of adverse events in stable patients with CAD and in ACS. Focusing on recent data, expression and activation of sPLA2-IIA in atherosclerotic lesions seemed to be one of the links between activated RAS, inflammation and the processes of lipid accumulation and lipid peroxidation in the vessel wall as main features of atherosclerosis. Therefore, direct inhibition of sPLA2-IIA through specific antagonists, or indirectly through AT1-receptor blockade, might be a new therapeutic option used to intervene in this detrimental process of plaque development. The confirmation of these therapeutic effects and their relevance in human atherosclerosis remain the foremost challenges.


References
Antonio V,Brouillet A,Janvier B,et al. Transcriptional regulation of the rat type IIA phospholipase A2 gene by cAMP and interleukin-1b in vascular smooth muscle cells: interplay of the CCAAT/enhancer binding protein (C/EBP), nuclear factor-kB and Ets transcription factorsBiochem J 2002;368:415–24. [pmid: 12188923]
Arbibe L,Koumanov K,Vial D,et al. Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interactionJ Clin Invest 1998;102:1152–60. [pmid: 9739049]
Aviram M,Maor I. Phospholipase A2-modified LDL is taken up at enhanced rate by macrophagesBiochim Biophys Res Commun 1992;185:465–72.
Balboa MA,Balsinde J,Winstead MV,et al. Novel group V phospholipase A2 involved in arachidonic acid mobilization in murine P388D1 macrophagesJ Biol Chem 1996;271:32381–4. [pmid: 8943302]
Balsinde J,Dennis EA. Inflammatory activation of arachidonic acid signaling in murine P388D1 macrophages via sphingomyelin synthesisJ Biol Chem 1997;272:20373–7. [pmid: 9252342]
Barbour SE,Dennis EA. Antisense inhibition of group II phospholipase A2 expression blocks the production of prostaglandin E2 by P388Dresden cellsJ Biol Chem 1993;268:21875–82. [pmid: 8408042]
Bezzine S,Koduri RS,Valentin E,et al. Exogenously added human group X secreted phospholipase A2 but not the group IB, IIA, and V enzymes efficiently release arachidonic acid from adherent mammalian cellsJ Biol Chem 2000;275:3179. [pmid: 10652303]
Boekholdt SM,Keller TT,Wareham NJ,et al. 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 StudyArterioscler Thromb Vasc Biol 2005;25:839–46. [pmid: 15692105]
Bonventre JV. The 85-kD cytosolic phospholipase A2 knockout mouse: a new tool for physiology and cell biologyJ Am Soc Nephrol 1999;10:404–12. [pmid: 10215342]
Cassis LA,Rateri DL,Lu H,et al. Bone marrow transplantation reveals that recipient AT1a receptors are required to initiate Angiotensin II?induced atherosclerosis and aneurysmsArterioscler Thromb Vasc Biol 2007;27:380–6. [pmid: 17158350]
Crowl RM,Stoller TJ,Conroy RR,et al. Induction of phospholipase A2 gene expression in human hepatoma cells by mediators of the acute-phase responseJ Biol Chem 1991;266:2647–51. [pmid: 1846631]
de Beer FC,de Beer MC,van der Westhuyzen DR,et al. Secretory non-pancreatic phospholipase A2: influence on lipoprotein metabolismJ Lipid Res 1997;38:2232–9. [pmid: 9392421]
de Beer FC,Connell PM,Yu J,et al. HDL modification by secretory phospholipase A2 promotes scavenger receptor class B type I interaction and accelerates HDL catabolismJ Lipid Res 2000;41:1849–57. [pmid: 11060355]
Divchev D,Grothusen Ch,Luchtefeld M,et al. Personal communication Impact of a combined treatment of angiotensin II type 1 receptor blockade and HMG-CoA-reductase inhibition on secretory phospholipase A2-type IIA and low density lipoprotein oxidation in patients with coronary artery diseaseEur Heart J. Manuscript Number: EURHEARTJ-D-07-01269, under review
Eckey R,Menschikowski M,Lattke P,et al. Minimal oxidation and storage of low density lipoproteins result in an increased susceptibility to phospholipid hydrolysis by phospholipase A2 Atherosclerosis 1997;132:165–76. [pmid: 9242962]
Fonteh AN,Bass DA,Marshall LA,et al. Evidence that secretory phospholipase A2 plays a role in arachidonic acid release and eicosanoid biosynthesis by mast cellsJ Immunol 1994;152:5438–46. [pmid: 8189063]
Fourcade O,Le Balle F,Fauvel J,et al. Regulation of secretory type-II phospholipase A2 and of lysophosphatidic acid synthesisAdv Enzyme Regul 1998;38:99–107. [pmid: 9762349]
Gesquiere L,Cho W,Subbaiah PV. Role of group IIA and group V secretory phospholipases A2 in the metabolism of lipoproteins. Substrate specificities of the enzymes and the regulation of their activities by sphingomyelinBiochemistry 2002;41:4911–20. [pmid: 11939786]
Granata F,Balestrieri B,Petraroli A,et al. Secretory phospholipases A2 as multivalent mediators of inflammatory and allergic disordersInt Arch Allergy Immunol 2003;131:153. [pmid: 12876405]
Green JA,Smith GM,Buchta R,et al. Circulating phospholipase A2 activity associated with sepsis and septic shock is indistinguishable from that associated with rheumatoid arthritisInflammation 1991;15:355–67. [pmid: 1757123]
Hakala JK,Oorni K,Pentikainen MO. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycansArterioscler Thromb Vasc Biol 2001;21:1053–8. [pmid: 11397719]
Han WK,Sapirstein A,Hung CC,et al. Cross-talk between cytosolic phospholipase A2 alpha (cPLA2 alpha) and secretory phospholipase A2 (sPLA2) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells: sPLA2 regulates cPLA2 alpha activity that is responsible for arachidonic acid releaseJ Biol Chem 2003;278:24153–63. [pmid: 12676927]
Hanasaki K,Yamada K,Yamamoto S,et al. Potent modification of low density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formationJ Biol Chem 2002;277:29116. [pmid: 12021277]
Hayakawa M,Kudo I,Tomita M,et al. Purification and characterization of membrane-bound phospholipase A2 from rat plateletsJ Biochem (Tokyo) 1988;103:263–6. [pmid: 3372490]
Hayek T,Aviram M,Heinrich R,et al. Losartan Inhibits Cellular Uptake of Oxidized LDL by Monocyte-Macrophages from Hypercholesterolemic PatientsBiochemical and Biophysical Research Communications 2000;273:417–20. [pmid: 10873620]
Heinecke JW,Suits AG,Aviram M,et al. Phagocytosis of lipase-aggregated low density lipoprotein promotes macrophage foam cell formation. Sequential morphological and biochemical eventsArterioscler Thromb 1991;11:1643–51. [pmid: 1657129]
Hernandez M,Burillo SL,Crespo MS,et al. Secretory phospholipase A2 activates the cascade of mitogen-activated protein kinases and cytosolic phospholipase A2 in the human astrocytoma cell line 1321N1J Biol Chem 1998;273:606. [pmid: 9417122]
Hidi R,Vargaftig BB,Touqui L. Increased synthesis and secretion of a 14-kDa phospholipase A2 by guinea pig alveolar macrophages: dissociation from arachidonic acid liberation and modulation by dexamethasoneJ Immunol 1993;151:56130–23.
Hurt-Camejo E,Andersen S,Standal R,et al. Localization of non-pancreatic secretory phospholipase A2 in normal and atherosclerotic arteries. Activity of the isolated enzyme on low-density lipoproteinsArterioscler Thromb Vasc Biol 1997;17:300–9. [pmid: 9081685]
Hurt-Camejo E,Camejo G,Peilot H,et al. Phospholipase A2 in vascular diseaseCirc Res 2001;89:298–304. [pmid: 11509445]
Ivandic B,Castellani LW,Wang XP,et al. Role of group II secretory phospholipase A2 in atherosclerosis. 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIA phospholipase A2Arterioscler Thromb Vasc Biol 1999;19:1284–90. [pmid: 10323781]
Jaross W,Eckey R,Menschikowski M. Biological effects of secretory phospholipase A(2) group IIA on lipoproteins and in atherogenesisEur J Clin Invest 2002;32:383–93. [pmid: 12059982]
Keidar S,Kaplan M,Hoffman A,et al. Ang-II stimulates macrophage-mediated oxidation of LDLAtherosclerosis 1995;115:201–15. [pmid: 7661879]
Keidar S,Attias J,Smith J,et al. The angiotensin-II receptor antagonist, losartan, inhibits LDL lipid peroxidation and atherosclerosis in apolipoprotein E-deficient miceBiochem Biophys Res Comm 1997;236:622–5. [pmid: 9245700]
Keidar S. Angiotensin, LDL peroxidation and AtherosclerosisLife Sciences 1998;63(l):l–11.
Keidar S,Attias J,Heinrich R,et al. Ang-II atherogenicity in E0 mice is associated with increased cellular cholesterol biosynthesisAtherosclerosis 1999;146:249–57. [pmid: 10532681]
Keidar S,Heinrich R,Kaplan M,et al. Angiotensin II administration to atherosclerotic mice increases macrophage uptake of oxidized LDL: a possible role for interleukin-6Arterioscler Thromb Vasc Biol 2001;21:1464–9. [pmid: 11557673]
Korotaeva AA,Samoilova EV,Kaminny AI,et al. The catalytically active secretory phospholipase A2 type IIA is involved in restenosis development after PTCA in human coronary arteries and generation of atherogenic LDLMol Cell Biochem 2005;270:107–113. [pmid: 15792359]
Kovanen PT,Pentikainen MO. Secretory group II phospholipase A2; a newly recognized acute-phase reactant with a role in atherogenesisCirc Res 2000;86:610–12. [pmid: 10746993]
Kudo I,Murakami M. Phospholipase A2 enzymesProstaglandins Other Lipid Mediat 2002;68-69:3–58. [pmid: 12432908]
Kugiyama K,Ota Y,Takazoe K,et al. Circulating levels of secretory type II phospholipase A(2) predict coronary events in patients with coronary artery diseaseCirculation 1999;100:1280–4. [pmid: 10491371]
Kugiyama K,Ota Y,Sugiyama S,et al. Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectorisAm J Cardiol 2000;86:718–22. [pmid: 11018189]
Kurihara H,Nakano T,Takasu N,et al. Intracellular localization of group II phospholipase A2 in rat vascular smooth muscle cells and its possible relationship to eicosanoid formationBiochim Biophys Acta 1991;1082:285–92. [pmid: 2029548]
Laine VJO,Grass DS,Nevalainen TJ. Protection by group II phospholipase A2 against Staphylococcus aureusJ Immunol 1999;162:7402–8. [pmid: 10358193]
Leitinger N,Watson AD,Hama SY,et al. Role of group II secretory phopholipase A2 in atherosclerosis: 2. Potential involvment of biologically active oxidized phospholipidsArterioscler Thromb Vasc Biol 1999;19:1291–8. [pmid: 10323782]
Leslie CC. Properties and regulation of cytosolic phospholipase A2J Biol Chem 1997;272:16709–12. [pmid: 9201969]
Liu PY,Li YH,Tsai WC,et al. Prognostic value and the changes of plasma levels of secretory type II phospholipase A2 in patients with coronary artery disease undergoing percutaneous coronary interventionEur Heart J 2003;24:1824–32. [pmid: 14563341]
Lowe LP,Greenland P,Ruth KJ,et al. Impact of major cardiovascular disease risk factors, particularly in combination, on 22-year mortality in women and menArch Intern Med 1998;158:2007–14. [pmid: 9778200]
Luchtefeld M,Bandlow N,Tietge UJ,et al. Angiotensin II type 1-receptor antagonism prevents type IIA secretory phospholipase A(2)-dependent lipid peroxidationAtherosclerosis 2006;25:25.
Mallat Z,Steg PG,Benessiano J,et al. Circulating secretory phospholipase A2 activity predicts recurrent events in patients with severe acute coronary syndromesJ Am Coll Cardiol 2005;46:1249–57. [pmid: 16198839]
Mallat Z,Benessiano J,Simon T,et al. Circulating secretory phospholipase A2 activity and risk of incident coronary events in healthy men and women: The EPIC-NORFOLK StudyArterioscler Thromb Vasc Biol 2007;27:1177–83. [pmid: 17303774]
Mehta JL,Li D. Facilitative interaction between angiotensin II and oxidized LDL in cultured human coronary artery endothelial cellsJ Renin Angiotensin Aldosterone Syst 2001;2:S70–S76.
Mehta JL,Li D. Identification, regulation and function of a novel lectin like oxidized low density lipoprotein receptorJ Am Coll Cardiol 2002;39:1429–1435. [pmid: 11985903]
Menschikowski M,Eckey R,Pietzsch J,et al. Expression of human secretory group IIA phospholipase A2 is associated with reduced concentrations of plasma cholesterol in transgenic miceInflammation 2000;24:227–37.
Menschikowski M,Rosner-Schiering A,Eckey R,et al. Expression of secretory group IIA phospholipase A(2) in relation to the presence of microbial agents, macrophage infiltrates, and transcripts of proinflammatory cytokines in human aortic tissuesArterioscler Thromb Vasc Biol 2000;20:751–62. [pmid: 10712401]
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. [pmid: 16516807]
Murakami M,Kudo I,Inoue K. Molecular nature of phospholipase A2 involved in prostaglandin I2 synthesis in human umbilical vein endothelial cells: possible participation of cytosolic and extracellular type II phospholipase A2J Biol Chem 1993;268:839–44. [pmid: 8419361]
Murakami M,Kudo I. New phospholipase A2 isozymes with a potential role in atherosclerosisCurr Opin Lipidol 2003;14:431–6. [pmid: 14501581]
Murakami M,Kudo I. Secretory phospholipase A2Biol Pharm Bull 2004;27:1158–64. [pmid: 15305013]
Nakano T,Ohara O,Teraoka H,et al. Glucocorticoids suppress group II phospholipase A2 production by blocking mRNA synthesis and post-transcriptional expressionJ Biol Chem 1990;265:12745–8. [pmid: 2373711]
Neaton JD,Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research GroupArch Intern Med 1992;152:56–64. [pmid: 1728930]
Nickenig G,Wassmann S,Bohm M. Regulation of the angiotensin AT1 receptor by hypercholesterolaemiaDiabetes Obes Metab 2000;2:223–8. [pmid: 11225655]
Niessen HW,Krijnen PA,Visser CA,et al. Type II secretory phospholipase A2 in cardiovascular disease: a mediator in atherosclerosis and ischemic damage to cardiomyocytes?Cardiovasc Res 2003;60:68. [pmid: 14522408]
Peilot H,Rosengren B,Bondjers G,et al. Interferon-g induces secretory group IIA phospholipase A2 in human arterial smooth muscle cells: involvement of cell differentiation, STAT-3 activation, and modulation by other cytokinesJ Biol Chem 2000;275:22895–904. [pmid: 10811652]
Pfeilschifter J,Pignat W,Vosbeck K,et al. Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat mesangial cellsBiochem Biophys Res Commun 1989;159:385–94. [pmid: 2784674]
Pickard RT,Strifler BA,Kramer RM,et al. Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A2J Biol Chem 1999;274:8823–31. [pmid: 10085124]
Pruzanski W,Stefanski E,Vadas P,et al. Regulation of the cellular expression of secretory and cytosolic phospholipases A2, and cyclooxygenase-2 by peptide growth factorsBiochim Biophys Acta 1998;1403:47–56. [pmid: 9622592]
Reddy ST,Herschman HR. Transcellular prostaglandin production following mast cell activation is mediated by proximal secretory phospholipase A2 and distal prostaglandin synthase 1J Biol Chem 1996;272:186–91. [pmid: 8550557]
Reddy ST,Herschman HR. Prostaglandin synthase-1 and prostaglandin synthase-2 are coupled to distinct phospholipases for the generation of prostaglandin D2 in activated mast cellsJ Biol Chem 1997;272:3231–7. [pmid: 9013559]
Romano M,Romano E,Bjorkerud S,et al. Ultrastructural localization of secretory type II phospholipase A2 in atherosclerotic and nonatherosclerotic regions of human arteriesArterioscler Thromb Vasc Biol 1998;18:519–25. [pmid: 9555856]
Rosengren B,Peilot H,Umaerus M,et al. Secretory phospholipase A2 type IIA and V in atherosclerosis: expression by vascular cells, localization in lesions and hydrolysis of lipoproteinsAtherosclerosis Suppl 2004;5:147.
Ross R. Atherosclerosis ? an inflammatory diseaseN Engl J Med 1999;340:115–26. [pmid: 9887164]
Sapirstein A,Bonventre JV. Specific physiological roles of cytosolic phospholipase A(2) as defined by gene knockoutsBiochim Biophys Acta 2000;1488:139–48. [pmid: 11080683]
Sartipy P,Bondjers G,Hurt-Camejo E. Phospholipase A2 type II binds to extracellular matrix biglycan: modulation of its activity on LDL by colocalization in glycosaminoglycan matrixesArteioscler Thromb Vasc Biol 1998;18:1934–41.
Sartipy P,Johansen B,Gasvik K,et al. Molecular basis for the association of group IIA phospholipase A2 and decorin in human atherosclerotic lesionsCirc Res 2000;86:707–14. [pmid: 10747008]
Schalkwijk C,Pfeilschifter J,M?rki F,et al. Interleukin 1?, tumor necrosis factor and forskolin stimulate the synthesis and secretion of group II phospholipase A2 in rat mesangial cellsBiochem Biophys Res Commun 1991;174:268–75. [pmid: 1989605]
Shoda J,Kano M,Asano T,et al. Secretory low-molecular-weight phospholipases A2 and their specific receptor in bile ducts of patients with intrahepatic calculi: factors of chronic proliferative cholangitisHepatology 1999;29:1026–36. [pmid: 10094942]
Silliman CC,Moore EE,Zallen G,et al. Presence of the M-type sPLA2 receptor on neutrophils and its role in elastase release and adhesionAm J Physiol Cell Physiol 2002;283:C1102. [pmid: 12225974]
Six DA,Dennis EA. The expanding superfamily of phospholipase A2 enzymes: classification and characterizationBiochim Biophys Acta 2000;1488:1–19. [pmid: 11080672]
Snitko Y,Yoon ET,Cho W. High specificity of human secretory class II phospholipase A2 for phosphatidic acidBiochem J 1997;321:737–41. [pmid: 9032461]
Sparrow CP,Parathasarathy S,Steinberg D. Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell-mediated oxidative modificationJ Lipid Res 1988;29:745–53. [pmid: 3139813]
Tada K,Murakami M,Kambe T,et al. Induction of cyclooxygenase-2 by secretory phospholipases A2 in nerve growth factor-stimulated rat serosal mast cells is facilitated by interaction with fibroblasts and mediated by a mechanism independent of their enzymatic functionsJ Immunol 1998;161:5008. [pmid: 9794438]
Taniguchi H,Momiyama Y,Ohmori R,et al. Associations of plasma C-reactive protein levels with the presence and extent of coronary stenosis in patients with stable coronary artery diseaseAtherosclerosis 2005;178:173–7. [pmid: 15585215]
Thomas F,Bean K,Guize L,et al. Combined effects of systolic blood pressure and serum cholesterol on cardiovascular mortality in young (<55 years) men and womenEur Heart J 2002;23:528–35. [pmid: 11922642]
Tietge UJF,Maugeais C,Cain W,et al. 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;275:10077–84. [pmid: 10744687]
Tietge UJ,Pratico D,Ding T,et al. Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stressJ Lipid Res 2005;46:1604. [pmid: 15897607]
Vadas P,Pruzanski W. Induction of group II phospholipase A2 expression and pathogenesis of the sepsis syndromeCirc Shock 1993;39:160–7. [pmid: 8490995]
Valentin E,Ghomashchi F,Gelb MH,et al. On the diversity of secreted phospholipases A(2). Cloning, tissue distribution, and functional expression of two novel mouse group II enzymesJ Biol Chem 1999;274:31195–202. [pmid: 10531313]
Vial D,Senorale-Pose M,Havet N,et al. Expression of type-II phospholipase A2 in alveolar macrophages: down-regulation by an inflammatory signalJ Biol Chem 1995;270:17327–32. [pmid: 7615534]
Webb NR. Secretory phospholipase A2 enzymes in atherogenesisCurr Opin Lipidol 2005;16:341–4. [pmid: 15891396]
Wooton-Kee CR,Boyanovsky BB,Nasser M,et al. Group V sPLA2 hydrolysis of LDL results in spontaneous particle aggregation and promotes macrophage foam cell formationArterioscler Thromb Vasc Biol 2004;24:762–7. [pmid: 14962950]
Wright GW,Ooi CE,Weiss J,et al. Purification of a cellular (granulocyte) and an extracellular (serum) phospholipase A2 that participate in the destruction of Escherichia coli in a rabbit inflammatory exudateJ Biol Chem 1990;265:6675–81. [pmid: 2182625]
Yuan Y,Jackson SP,Newnham HH,et al. An essential role for lysophosphatidylcholine in the inhibition of platelet aggregation by secretory phospholipase A2Blood 1995;86:4166–74. [pmid: 7492774]

Article Categories:
  • Review

Keywords: secretory phospholipase A2, lipoproteins, renin-angiotensin system, inflammation, atherosclerosis.

Previous Document:  Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers.
Next Document:  Cardiovascular co-morbidity in rheumatic diseases.