An Oxidized Derivative of Phosphatidylcholine is a Substrate for the Platelet-Activating Factor Acetylhydrolase from Human Plasma

Stremler, Kay E.; Stafforini, Diana M.; Prescott, Stephen M.; Zimmerman, Guy A.; McIntyre, Thomas M.

doi:10.1016/s0021-9258(18)83548-7

Cited by 214 publications

(30 citation statements)

References 17 publications

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“…4HNE is a lipid peroxidation product of polyunsaturated fatty acids formed during the oxidation of LDL or membranes (Uchida, 2003). Oxidized phosphatidylcholine (oxPC), the most abundant oxidized phospholipid in ox-LDL, is a specific substrate for PLA2 (Stremler et al, 1989). NADPH oxidase and MPO are the most important superoxide (O 2 -)-producing enzymes in hypertension and atherosclerosis (Cai et al, 2003;Nicholls and Hazen, 2005).…”

Section: Discussionmentioning

confidence: 99%

Periodontal Pathogen Accelerates Lipid Peroxidation and Atherosclerosis

et al. 2013

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Recent studies have shown an association between periodontal disease and cardiovascular disease. We previously reported that intravenous challenge with Aggregatibacter actinomycetemcomitans (Aa) accelerated atherosclerosis in apolipoprotein E-deficient spontaneously hyperlipidemic (Apoe(shl)) mice. In this study, we investigated whether live cells were required for atherosclerosis induction or whether lipopolysaccharide (LPS) alone was sufficient to increase atherosclerotic damage. Mice were injected intravenously with live Aa HK1651, heat-killed (H.K.) Aa, or Aa LPS 3 times a week for 3 weeks and were sacrificed at 15 weeks of age. The areas of the aortic sinus that were covered with atherosclerotic plaques were significantly larger in mice treated with live Aa, H.K. Aa, or Aa LPS compared with vehicle-challenged mice. The order of the extent of atherosclerosis was live Aa > H.K. Aa > Aa LPS > sham. Toll and nucleotide oligomerization domain (NOD)-like receptor mRNA expression significantly increased in the live Aa, H.K. Aa, and Aa LPS treatment groups. Aa challenge markedly promoted the oxidation of LDL through oxidative stress involving NADPH oxidase- and myeloperoxidase-derived reactive oxygen species. These results suggested that Aa promoted innate immune signaling and low-density lipoprotein (LDL) oxidation and may facilitate atheroma development.

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Section: Discussionmentioning

confidence: 99%

Periodontal Pathogen Accelerates Lipid Peroxidation and Atherosclerosis

et al. 2013

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“…Oxidation of LDL to modified particles is now a cornerstone of our understanding of the early steps in atherogenesis (51)(52)(53) and one result of the oxidation of LDL is an increase in the content of lysophosphatidylcholine from 1% to 5% of the total phosphatidylcholine content to 40% to 50% of this pool (3,54,55). Oxidatively fragmented phospholipids generated in this process are substrates (4,5,49,(56)(57)(58) for the LDL-associated (59) PAF acetylhydrolase, which is responsible for this increase in its hydrolysis product (30,56,58). Among the reported effects of lysophosphatidylcholine associated with oxidized LDL particles is an impairment of endothelial-dependent vasorelaxation in ex vivo arterial preparations (3,60), as well as antibody and cytokine production by cells of the immune system (7).…”

Section: Discussionmentioning

confidence: 99%

“…Most of the circulating lysophosphatidylcholine is likely bound to albumin, but some is associated with lipoprotein particles, where it comprises 1% to 5% of the total phosphatidylcholine content of LDL particles. Oxidation and fragmentation of the polyunsaturated sn -2 fatty acyl residues of phosphatidylcholine, followed by the hydrolysis of the shortened fatty acyl residues by LDL-associated platelet-activating factor (PAF) acetylhydrolase (4,5), also increase the content of lysophosphatidylcholine during the oxidative modification of LDL that accompanies their conversion to atherogenic particles (6).…”

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confidence: 99%

Lysophosphatidylcholine and lyso-PAF display PAF-like activity derived from contaminating phospholipids

Marathe

Silva

Neto

et al. 2001

Journal of Lipid Research

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Lysophosphatidylcholine is an abundant component of plasma and oxidized LDL that displays several biological activities, some of which may occur through the platelet-activating factor (PAF) receptor. We find that commercial lysophosphatidylcholine, its alkyl homolog (lyso-PAF), and PAF all induce inflammation in a murine model of pleurisy. Hydrolysis of PAF to lyso-PAF by recombinant PAF acetylhydrolase abolished this eosinophilic infiltration, implying that lyso-PAF should not have displayed inflammatory activity. Saponification of lyso-PAF or PAF acetylhydrolase treatment of lyso-PAF or lysophosphatidylcholine abolished activity; neither lysolipid should contain susceptible sn -2 residues, suggesting contaminants account for the bioactivity. Lyso-PAF and to a lesser extent lysophosphatidylcholine stimulated Ca 2 ؉ accumulation in 293 cells stably transfected with the human PAF receptor, and this was inhibited by specific PAF receptor antagonists. Again, treatment of lyso-PAF or lysophosphatidylcholine with recombinant PAF acetylhydrolase, a nonselective phospholipase A 2 , or saponification of lyso-PAF destroyed the PAF-like activity, a result incompatible with lyso-PAF or lysophosphatidylcholine being the actual agonist.We conclude that neither lyso-PAF nor lysophosphatidylcholine is a PAF receptor agonist, nor are they inflammatory by themselves. We suggest that PAF or a PAF-like mimetic accounts for inflammatory effects of lysophosphatidylcholine and lyso-PAF. -Marathe, G.

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“…PLA2G7 hydrolyzes the sn-2 acetyl group from PAF or oxidatively truncated sn-2 acyl chains on PCs such as az-PAF in vitro, with no activity on medium to long-chain acyl chains (Fig. 3A) 125,128,129 . This lipase generates pro-inflammatory lysophosphatidylcholine (LPC) and fatty acids as products.…”

Section: Pla2g7mentioning

confidence: 99%

Lipases and their inhibitors in health and disease

Nomura

Casida

2016

Chemico-Biological Interactions

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Lipids play diverse and important biological roles including maintaining cellular integrity, storing fat for energy, acting as signaling molecules, and forming microdomains to support membrane protein signaling. Altering the levels of specific lipid species through activating or inactivating their biosynthetic or degradative pathways has been shown to provide either therapeutic benefit or cause disease. This review focuses on the functional, therapeutic, and (patho)physiological roles of lipases within the serine hydrolase superfamily and their inhibitors, with particular emphasis on the pharmacological tools, drugs, and environmental chemicals that inhibit these lipases.

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An Oxidized Derivative of Phosphatidylcholine is a Substrate for the Platelet-Activating Factor Acetylhydrolase from Human Plasma

Cited by 214 publications

References 17 publications

Periodontal Pathogen Accelerates Lipid Peroxidation and Atherosclerosis

Periodontal Pathogen Accelerates Lipid Peroxidation and Atherosclerosis

Lysophosphatidylcholine and lyso-PAF display PAF-like activity derived from contaminating phospholipids

Lipases and their inhibitors in health and disease

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