Secretory Phospholipase A₂Group V

Abstract

Objective-To study the distribution of group V secretory phospholipase A 2 (sPLA 2 ) in human and mouse lesions and compare its expression by human vascular cells, its activity toward lipoproteins, and the interaction with arterial proteoglycans (proteoglycans) with those of sPLA 2 -IIA. In addition, we also investigated the effect of a Western diet and lipopolysaccharide challenge on the aortic expression of these enzymes in mouse models. Methods and Results-Immunohistochemistry showed sPLA 2 -V in human and mouse lesions to be associated with smooth muscle cells and also surrounding foam cells in lipid core areas. mRNA of the enzyme was expressed in human lesions and human vascular cells, supporting the immunohistochemistry data. sPLA 2 -V but not sPLA 2 -IIA was active on lipoproteins in human serum. The association with proteoglycans enhanced 2-to 3-fold sPLA 2 -V activity toward low-density lipoproteins but not that of the group IIA enzyme. Experiments in mouse models showed that treatment with a Western diet induced expression of sPLA 2 -V but not that of sPLA 2 -IIA in aorta. On the other hand, lipopolysaccharide-induced acute inflammation augmented the expression of sPLA 2 -IIA but not that of sPLA 2 -V. Key Words: phospholipase Ⅲ atherogenesis Ⅲ inflammation Ⅲ lipoprotein-retention Ⅲ proteoglycans D uring atherosclerosis development, there is a progressive decrease of the lesion phospholipid content and enrichment in cholesterol. 1 Furthermore, apolipoprotein B (apoB) lipoproteins isolated from human and rabbit lesions contain less phosphatidylcholine (PC) and more sphingomyelin than circulating lipoproteins. 2,3 Therefore, lipoproteins trapped in the intima appear to be hydrolyzed by secretory phospholipases. 4 These enzymes may contribute to atherosclerosis by hydrolysis of low-density lipoprotein (LDL) phospholipids that induce fusion and increase binding of cholesterol-rich particles to intima proteoglycans, triggering further modifications. [5][6][7][8] In addition, phospholipase(s) A 2 contribute to local release of lyso-phospholipids and nonesterified fatty acids, which have proinflammatory properties in arterial cells. 9 -12 Conclusions-These See page 1421Secretory phospholipase A 2 (sPLA 2 ) group IIA is present in human atherosclerotic lesions, and experimental and clinical evidence suggest its involvement in atherosclerosis and cardiovascular disease. 13-17 sPLA 2 -IIA and the more recently cloned sPLA 2 -V are members of a family of enzymes that hydrolyze the fatty acids at the sn-2 position of glycerophospholipids. Both enzymes have low molecular weight (14 kDa), are histidine and calcium dependent, rich in disulfide bonds, are basic, and share structure similarities. 18 Several of these properties stabilize and enhance their activity in the extracellular milieu. The genes of sPLA 2 -IIA and sPLA 2 -V enzymes are located at close positions in homologous regions in mouse chromosome 4 and human chromosome 1 and share the same promoter. 19 This region was identified as an atherosclerosis ...

Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

“…ApoB may be particularly susceptible to modification by lipid peroxides inside hepatocytes, both because it would be assembled into close contact with them and because the unique structure of apoB facilitates its aggregation under a wide range of physiologic (e.g., Figs. 1 and 2), pathogenic, and even artificial stimuli that do not affect other proteins to the same extent (4,(42)(43)(44)(45)(46)(47). Its remarkable susceptibility to aggregation allows a normal hypolipidemic response to dietary PUFAs and other stimuli ( Fig.…”

Calcium-Independent Phospholipase A2β-Akt Signaling Is Involved in Lipopolysaccharide-Induced NADPH Oxidase 1 Expression and Foam Cell Formation

“…Very recently, it was reported that syndecan-4 controls uptake of modified LDL by group V sPLA 2 (45). The overall mechanism of sPLA 2 in foam cell formation is suggested to comprise modification of lipoproteins (46,47) or sPLA 2 -hydrolyzed lysophosphatidylcholine (LPC) (48). However, our results show that LPS-induced iPLA 2 ␤ activation increases Nox1 expression, thereby increasing ROS production and that foam cell conversion eventually occurs with the cotreatment of LPS and LDL.…”

PLA 2 -V

“…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 PLA 2 -induced aggregation and fusion of LDL particles, 22 and an enhanced interaction of sPLA 2 -V-treated LDL to proteoglycans has been demonstrated by Rosengren et al 15 In terms of atherogenesis, the full repertoire of the ApoB-100 -containing lipoproteins enter the arterial intima and become entrapped within the subendothelial proteoglycan meshwork. A subendothelially located macrophage synthesizes and secretes sPLA 2 -V, which hydrolyzes the phosphatidylcholines on the surface of the entrapped lipoproteins.…”

“…In contrast, sPLA 2 -V has been shown to efficiently hydrolyze native LDL. 14,15 Most importantly, sPLA 2 -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.…”

“…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 sPLA 2 -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 sPLA 2 enzymes.…”