Distinctiveness of secretory phospholipase A2 group IIA and V suggesting unique roles in atherosclerosis

Rosengren, Birgitta; Jönsson‐Rylander, Ann‐Cathrine; Peilot, H.; Camejo, Germán; Hurt-Camejo, Eva

doi:10.1016/j.bbalip.2006.06.008

Cited by 55 publications

(50 citation statements)

References 74 publications

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“…These results are in accordance with previously published data (41)(42)(43)(44). In comparison, the rank order of anti-Plasmodium toxicity was hGX Ͼ hGIIF Ͼ hGIII Ͼ hGV Ͼ hGIB, hGIIA, hGIID, hGIIE, hGXIIA, and hGXIIB in plasma.…”

Section: Discussionsupporting

confidence: 81%

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂

et al. 2015

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We have previously shown that secreted phospholipases A 2 (sPLA 2 s) from animal venoms inhibit the in vitro development of Plasmodium falciparum, the agent of malaria. In addition, the inflammatory-type human group IIA (hGIIA) sPLA 2 circulates at high levels in the serum of malaria patients. However, the role of the different human sPLA 2 s in host defense against P. falciparum has not been investigated. We show here that 4 out of 10 human sPLA 2 s, namely, hGX, hGIIF, hGIII, and hGV, exhibit potent in vitro anti-Plasmodium properties with half-maximal inhibitory concentrations (IC 50 s) of 2.9 ؎ 2.4, 10.7 ؎ 2.1, 16.5 ؎ 9.7, and 94.2 ؎ 41.9 nM, respectively. Other human sPLA2s, including hGIIA, are inactive. The inhibition is dependent on sPLA 2 catalytic activity and primarily due to hydrolysis of plasma lipoproteins from the parasite culture. Accordingly, purified lipoproteins that have been prehydrolyzed by hGX, hGIIF, hGIII, and hGV are more toxic to P. falciparum than native lipoproteins. However, the total enzymatic activities of human sPLA 2 s on purified lipoproteins or plasma did not reflect their inhibitory activities on P. falciparum. For instance, hGIIF is 9-fold more toxic than hGV but releases a lower quantity of nonesterified fatty acids (NEFAs). Lipidomic analyses of released NEFAs from lipoproteins demonstrate that sPLA 2 s with anti-Plasmodium properties are those that release polyunsaturated fatty acids (PUFAs), with hGIIF being the most selective enzyme. NEFAs purified from lipoproteins hydrolyzed by hGIIF were more potent at inhibiting P. falciparum than those from hGV, and PUFA-enriched liposomes hydrolyzed by sPLA 2 s were highly toxic, demonstrating the critical role of PUFAs. The selectivity of sPLA 2 s toward lowand high-density (LDL and HDL, respectively) lipoproteins and their ability to directly attack parasitized erythrocytes further explain their anti-Plasmodium activity. Together, our findings indicate that 4 human sPLA 2 s are active against P. falciparum in vitro and pave the way to future investigations on their in vivo contribution in malaria pathophysiology.

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Section: Discussionsupporting

confidence: 81%

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂

et al. 2015

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“…It has been pointed out that the characteristic differences between group IIA and group V sPLA 2 in hydrolyzing lipoprotein phospholipids appear to be due to the presence of tryptophan residues, especially Trp31, and a glycine residue, Gly53, in the interfacial binding region of group V sPLA 2 , which are absent in group IIA sPLA 2 (34,35). Such structural dissimilarity increases the ability of group V sPLA 2 to penetrate PtdCho monolayers, and explains why human group V sPLA 2 , but not group IIA sPLA 2 , can hydrolyze this major phospholipid in outer plasma membranes in mammalian cells and lipoproteins (3,36,37).…”

Section: Role Of Membrane and Enzyme Structurementioning

confidence: 99%

Phase composition of lipoprotein SM/cholesterol/PtdCho affects FA specificity of sPLA2s

Kuksis

Pruzanski

2008

Journal of Lipid Research

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We have previously reported preferential release of polyunsaturated FAs during hydrolysis of lipoprotein phosphatidylcholine (PtdCho) by group X secretory phospholipase A 2 (sPLA 2 ) and preferential release of oligounsaturated FAs during hydrolysis of lipoprotein PtdCho by group V sPLA 2 , but the mechanism of this selectivity has remained unknown. We now show that the rate and specificity of hydrolysis are affected by relative increases in endogenous SM and free cholesterol (FC) during the lipase digestion. The highest preference for arachidonate release from LDL and HDL by group X sPLA 2 was observed for residual SM/PtdCho molar ratio of 1.2 and 0.4, compared with the respective starting ratios of 0.4 and 0.2, as measured by liquid chromatography/electrospray ionization-mass spectrometry. Group V sPLA 2 showed preferential release of linoleate from LDL and HDL at SM/PtdCho ratio 1.5 and 0.6, respectively. We have attributed the change in FA specificity to segregation of molecular species of PtdCho and of sPLA 2 s between disordered and ordered SM/FC/ PtdCho lipid phases. The increases in SM and FC during digestion with group IIA sPLA 2 were more limited, and a preferential hydrolysis of any FAs was not observed. A preferential release of linoleate during hydrolysis of phosphatidylcholine (PtdCho) by group V secretory phospholipase A 2 (sPLA 2 ) was first reported in liposomal (1-3) and later in lipoprotein (4-6) incubations, but the mechanism of this selectivity has remained unknown. Early work (1, 2) attributed the selective enzyme activity to a difference in the physical state of substrate between the sonicate and the natural membranes that may contain a more optimum mixture of phospholipids. Alternatively, a preferential release of arachidonate by group V sPLA 2 exogenously added to cell cultures has been attributed to its combined action with cytosolic PLA 2 (7). Subsequent work with liposomes suggested a special role for ceramides (3) in regulation of group V sPLA 2 hydrolysis of plasma PtdCho, which, however, was difficult to reconcile with the apparent absence of sphingomyelinase activity from plasma lipoproteins (6,8,9). Likewise, the apparent preferential release of PtdCho arachidonate by group X sPLA 2 during liposomal (10, 11), lipoprotein (4-6), and cellular (10, 12) incubations has remained unexplained. In contrast, group IIA sPLA 2 apparently attacked liposomal and lipoprotein PtdCho without FA discrimination, although at a significantly lower rate than group V and group X sPLA 2 s (3,5,9,10,12). Therefore, the true differences in the activity and apparent FA specificity of PtdCho hydrolysis by the sPLA 2 s have remained obscure.In other studies, a preferential release of arachidonate by group IIA sPLA 2 from phosphatidylethanolamine/ phosphatidylserine (PtdEtn/PtdSer) micelles was observed (13,14) in the presence of added SM/ceramide and was attributed to phase separation and exclusion of polyunsaturates from the ordered liquid phase formed under these conditions. The inhibitory effect...

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“…8 Like S-SMase, sPLA 2 is expressed in animal and human atheromata, and lipoproteins extracted from atherosclerotic lesions show evidence of PLA 2 -mediated hydrolysis. Lipoproteins hydrolyzed by sPLA 2 in vitro are more susceptible to fusion, show a higher affinity for arterial wall-derived proteoglycans, and can promote macrophage foam cell formation.…”

Section: Secretory Phospholipase Amentioning

confidence: 99%

“…For example, our understanding of the molecular basis of lipoprotein retention has expanded greatly, particular with regard to the roles of specific subendothelial chondroitin sulfate (CS) proteoglycans and accessory molecules within the arterial wall. [3][4][5][6][7][8] Of major significance, studies in genetically engineered mice have established a causal relationship between lipoproteinmatrix interactions and early atherogenesis (see section below on lipoprotein retention). 9,10 Moreover, a recent autopsy study of children and young adults who died of noncardiac causes showed a spectrum of changes in the subendothelium of susceptible areas within the right coronary artery, ranging from no lipid to very small amounts of lipoprotein-derived lipid with no inflammatory cells to larger amounts lipoprotein lipids associated with the first signs of macrophage infiltration and then finally to conversion of these macrophages into frank foam cells (Figure 2).…”

mentioning

confidence: 99%

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

2007

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Abstract-The key initiating process in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Local biological responses to these retained lipoproteins, including a chronic and maladaptive macrophageand T-cell-dominated inflammatory response, promote subsequent lesion development. The most effective therapy against atherothrombotic cardiovascular disease to date-low density lipoprotein-lowering drugs-is based on the principle that decreasing circulating apolipoprotein B lipoproteins decreases the probability that they will enter and be retained in the subendothelium. Ongoing improvements in this area include more aggressive lowering of low-density lipoprotein and other atherogenic lipoproteins in the plasma and initiation of low-density lipoprotein-lowering therapy at an earlier age in at-risk individuals. Potential future therapeutic approaches include attempts to block the interaction of apolipoprotein B lipoproteins with the specific subendothelial matrix molecules that mediate retention and to interfere with accessory molecules within the arterial wall that promote retention such as lipoprotein lipase, secretory sphingomyelinase, and secretory phospholipase A 2 . Although not the primary focus of this review, therapeutic strategies that target the proatherogenic responses to retained lipoproteins and that promote the removal of atherogenic components of retained lipoproteins also hold promise. The finding that certain human populations of individuals who maintain lifelong low plasma levels of apolipoprotein B lipoproteins have an Ϸ90% decreased risk of coronary artery disease gives hope that our further understanding of the pathogenesis of this leading killer could lead to its eradication.

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Distinctiveness of secretory phospholipase A2 group IIA and V suggesting unique roles in atherosclerosis

Cited by 55 publications

References 74 publications

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂

Phase composition of lipoprotein SM/cholesterol/PtdCho affects FA specificity of sPLA2s

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

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Distinctiveness of secretory phospholipase A2 group IIA and V suggesting unique roles in atherosclerosis

Cited by 55 publications

References 74 publications

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A 2

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A 2

Phase composition of lipoprotein SM/cholesterol/PtdCho affects FA specificity of sPLA2s

Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis

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Product

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In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂