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The capacity of group V sPLA2 to increase atherogenicity of ApoE-/- and LDLR-/- mouse LDL in vitro predicts its atherogenic role in vivo.

ABSTRACT: In vitro data indicate that human LDL modified by Group V secretory phospholipase A(2) (GV sPLA(2)) is proatherogenic. Consistent with this, gain and loss of function studies demonstrated that GV sPLA(2) promotes atherosclerosis in LDLR(-/-) mice. The current study investigates whether GV sPLA(2) promotes atherosclerotic processes in apoE(-/-) mice.LDL (d=1.019 to 1.063) from apoE(-/-) and LDLR(-/-) mice fed chow or Western diet were hydrolyzed by GV sPLA(2). Phosphatidylcholine on LDL from LDLR(-/-) mice fed either a chow or Western diet was hydrolyzed to a greater extent (61.1+/-0.4% and 45.3+/-4.6%) than the corresponding fractions from apoE(-/-) mice (41.7+/-3.6% and 39.4+/-1.2%). ApoE(-/-) LDL induced macrophage foam cell formation in vitro without modification by GV sPLA(2), whereas hydrolysis of LDLR(-/-) LDL was a prerequisite for foam cell formation. In contrast to findings in LDLR(-/-) mice, GV sPLA(2) deficiency did not significantly reduce atherosclerosis in apoE(-/-) mice, although collagen content was significantly reduced in lesions of apoE(-/-) mice lacking GV sPLA(2).The ability of GV sPLA(2) to promote atherosclerotic lipid deposition in apoE(-/-) and LDLR(-/-) mice may be related to its ability to increase the atherogenic potential of LDL from these mice as assessed in vitro.

SUBMITTER: Boyanovsky B

PROVIDER: S-EPMC2782483 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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The capacity of group V sPLA2 to increase atherogenicity of ApoE-/- and LDLR-/- mouse LDL in vitro predicts its atherogenic role in vivo.

Boyanovsky Boris B Zack Melissa M Forrest Kathy K Webb Nancy R NR

Arteriosclerosis, thrombosis, and vascular biology 20090122 4

<h4>Objective</h4>In vitro data indicate that human LDL modified by Group V secretory phospholipase A(2) (GV sPLA(2)) is proatherogenic. Consistent with this, gain and loss of function studies demonstrated that GV sPLA(2) promotes atherosclerosis in LDLR(-/-) mice. The current study investigates whether GV sPLA(2) promotes atherosclerotic processes in apoE(-/-) mice.<h4>Methods and results</h4>LDL (d=1.019 to 1.063) from apoE(-/-) and LDLR(-/-) mice fed chow or Western diet were hydrolyzed by GV ...[more]

PMID: 19164803

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Project description:Electronegative low-density lipoprotein (LDL(-)) has been found in the plasma of familial hypercholesterolemia and acute myocardial infarction and has been implicated in atherosclerosis and cardiovascular disease. However, less is known about the involvement of LDL(-) in atherosclerosis-related inflammation. This study aims at investigating the inducibility of LDL(-) by atherogenic diet in rabbits and at exploring the proinflammatory potential of the diet-induced LDL(-) in macrophages. Rabbits were fed with an atherogenic diet; LDL was isolated from plasma by NaBr density gradient ultracentrifugation and was then resolved into nLDL and LDL(-) by anion-exchange chromatography. Isolated nLDL and LDL(-) were directly used or incubated with 10 ?M CuSO4 for 24?h to produce copper- (Cu-) ox-nLDL and Cu-ox-LDL(-). The effects of these LDLs on inflammation were evaluated in THP-1-derived macrophages. Macrophages were treated with nLDL, LDL(-), and extensively oxidized LDL (ox-LDL), then the levels of interleukin- (IL-) 1?, IL-6, and tumor necrosis factor- (TNF-) ? in a culture medium were determined by ELISA, and the levels of total and phosphorylated I?B, p65, p38, JNK, and ERK in cell lysates were determined by Western blotting. The LDL(-) induced significantly higher levels of IL-1?, IL-6, and TNF-? in the medium. The levels of phosphorylated/total I?B, p65, p38, JNK, and ERK were also upregulated by LDL(-). In contrast, nLDL, Cu-ox-nLDL, and Cu-ox-LDL(-) exhibited much less effect. Knockdown of lectin-type oxidized LDL receptor- (LOX-) 1 resulted in significant reduction in LDL(-)-induced IL-1?, IL-6, and TNF-?. In addition, these LDL(-) effects were also markedly attenuated by inhibition of NF-?B and ERK1/2. The data suggested that LDL(-) induced inflammation through LOX-1-, NF-?B-, and ERK1/2-dependent pathways. Taken together, our results show that rabbits fed with atherogenic diet produce a highly proinflammatory LDL(-) that is more potent in inducing inflammation than nLDL and extensively oxidize LDL in macrophages. The results thus provide a novel link between diet-induced hypercholesterolemia and inflammation.

Dataset Information

The capacity of group V sPLA2 to increase atherogenicity of ApoE-/- and LDLR-/- mouse LDL in vitro predicts its atherogenic role in vivo.

Publications

The capacity of group V sPLA2 to increase atherogenicity of ApoE-/- and LDLR-/- mouse LDL in vitro predicts its atherogenic role in vivo.

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