Oxidative modification of low density lipoprotein in normal and hyperlipidemic patients: effect of lysophosphatidylcholine composition on vascular relaxation

Chen, L.; Liang, Binhua; Froese, D. E.; Liu, S.; Wong, Johnson; Tran, Khai; Hatch, Grant M.; Mymin, David; Kroeger, Edwin A.; Man, Ryk; Choy, Patrick C.

doi:10.1016/s0022-2275(20)37262-x

Cited by 89 publications

(23 citation statements)

References 33 publications

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“…Our data also indicate that LDL-associated lysophospholipids can serve as direct substrates for ATX. LPC constitutes only 1-5% of the total phosphatidylcholine associated with LDL, but this is increased substantially by oxidation under which conditions 40-50% of LDL-associated phosphatidylcholine can be converted to LPC (52). Oxidation might therefore result in increased ATX-catalyzed generation of LDL-associated LPA because of this increase in substrate availability.…”

Section: Discussionmentioning

confidence: 99%

Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid

Kræmer

Mao

Hammill

et al. 2019

Journal of Lipid Research

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Supplementary key words cholesterol • lipoprotein • low density lipoprotein • autotaxin • mass spectrometryLysophosphatidic acids (LPAs) are a class of small receptor active phospholipid signaling molecules that promote the growth, survival, and motility of many cell types. LPA, its receptors and enzymes involved in LPA generation and inactivation are implicated in many pathologies including cardiovascular, pulmonary, and neurological diseases, and cancer (1-3). These observations underscore the importance of identifying the sources and mechanisms regulating the bioavailability and signaling actions of LPA that underlie this association with disease processes. LPA is abundant in plasma where it is primarily generated by hydrolysis of lysophospholipids [notably lysophosphatidylcholine (LPC)] by the secreted phospholipase, autotaxin (ATX) (4, 5), and can be degraded by phospholipases and lipid phosphatases, which may contribute to turnover of circulating LPA pools (3, 4). There is significant inter-individual variability in plasma LPA levels in humans (6). Despite some provocative observations, efforts to associate plasma LPA levels with human disease risk have largely been unsuccessful (7). Plasma LPA is prominently associated with serum albumin (6). Lysophospholipids are present in HDLs and LDLs (8); and LDL, particularly oxidized LDL, contains bioactive LPA (9, 10). This association of LPA with LDL is particularly relevant to the possible role of LPA in cardiovascular disease because of the central role played by LDL in atherosclerosis. However, at present, little is known about the metabolism and function of LDL-associated LPA.Understanding the regulation of LPA metabolism and signaling in cardiovascular disease is important because, in humans, heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3), an enzyme that can Abstract Lysophosphatidic acids (LPAs) are bioactive radyl hydrocarbon-substituted derivatives of glycerol 3-phosphate. LPA metabolism and signaling are implicated in heritable risk of coronary artery disease. Genetic and pharmacological inhibition of these processes attenuate experimental atherosclerosis. LPA accumulates in atheromas, which may be a consequence of association with LDLs. The source, regulation, and biological activity of LDL-associated LPA are unknown. We examined the effects of experimental hyperlipidemia on the levels and distribution of circulating LPA in mice. The majority of plasma LPA was associated with albumin in plasma from wild-type mice fed normal chow. LDL-associated LPA was increased in plasma from high-fat Western diet-fed mice that are genetically prone to hyperlipidemia (LDL receptor knockout or activated proprotein convertase subtilisin/kexin type 9-overexpressing C57Bl6). Adipose-specific deficiency of the ENPP2 gene encoding the LPA-generating secreted lysophospholipase D, autotaxin (ATX), attenuated these Western diet-dependent increases in LPA. ATX-dependent increases in LDLassociated LPA were observed in isolated incubated plasma. ...

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Section: Discussionmentioning

confidence: 99%

Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid

Kræmer

Mao

Hammill

et al. 2019

Journal of Lipid Research

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“…These can migrate during chromatography much like lysophosphatidylcholine, can be isobaric contaminants, and-being quite potent-are exceedingly difficult to detect at low levels in the bulk lipid preparation. Some of the activity ascribed to lysophosphatidylcholine appears to act through the PAF receptor because previous work showed that in vivo vasodilatation (3,27) and edema (28) induced by lysophosphatidylcholines are blocked by PAF receptor antagonists. A role for the PAF receptor in responding to lysophosphatidylcholine is directly addressed in isolated macrophages or Chinese hamster ovary cells ectopically expressing the human PAF receptor, where the Ca 2ϩ increase induced in these cells by lysophosphatidylcholine is blocked by a PAF receptor antagonist (24).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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). However, inhibition of vasodilation by PAF receptor antagonists in vivo (3,27), coupled with the inability of lysophosphatidylcholine to activate the PAF receptor as shown here, suggests that LDL-associated lysophosphatidylcholine also is not vasoactive, at least through the PAF receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Lysophosphatidylcholine is an abundant plasma component. Independent methods of analysis place the value in normal blood between 140 to 150 M (1, 2), and it accumulates to millimolar levels in hyperlipidemic subjects (3). 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.…”

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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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Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using ¹H‐NMR‐ and MS‐based metabolomics

Li¹,

Zhao²,

Jiang³

et al. 2020

Biomedical Chromatography

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Duzhong Jiangya Tablet (DJT) composed of Eucommia ulmoides Oliv. and several other traditional Chinese medicines is a Chinese herbal compound, which is clinically used to treat hypertension. The aim of this study was to evaluate the antihypertensive effect of DJT and amlodipine besylate (AB) on the synergistic treatment of spontaneously hypertensive rats (SHRs), and to explore its antihypertensive mechanism. The synergistic therapeutic effect of DJT in combination with AB on SHR was studied using two metabolomics methods based on mass spectrum (MS) and nuclear magnetic resonance. Metabolomics analysis of plasma, urine, liver, and kidney and the combination of orthogonal partial least squares discriminant analysis was performed to expose potential biomarkers. Then, the overall metabolic characteristics and related abnormal metabolic pathways in hypertensive rats were constructed. Blood pressure measurements showed that DJT combined with AB has better effects in treating hypertension than it being alone. A total of 30 biomarkers were identified, indicating that hypertension disrupted the balance of multiple metabolic pathways in the body, and that combined administration restored metabolite levels better than their administration alone. The changes of biomarkers revealed the synergistic therapeutic mechanism of DJT combined with AB, which provided a reference for the combination of Chinese and Western medicines.

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Oxidative modification of low density lipoprotein in normal and hyperlipidemic patients: effect of lysophosphatidylcholine composition on vascular relaxation

Cited by 89 publications

References 33 publications

Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid

Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid

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

Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using ¹H‐NMR‐ and MS‐based metabolomics

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Oxidative modification of low density lipoprotein in normal and hyperlipidemic patients: effect of lysophosphatidylcholine composition on vascular relaxation

Cited by 89 publications

References 33 publications

Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid

Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid

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

Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using 1H‐NMR‐ and MS‐based metabolomics

Contact Info

Product

Resources

About

Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using ¹H‐NMR‐ and MS‐based metabolomics