Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration (original) (raw)
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Alkyl-glycerol supplementation rescues pathology in peripheral organs of ether-lipid deficient mice
2009
Plasmalogens are ether-phospholipids which serve as endogenous antioxidants and have an important structural role in mediating membrane dynamics . Plasmalogen deficiency is the biochemical hallmark of the peroxisomal disorder Rhizomelic Chondrodysplasia Punctata (RCDP), but other genetic and developmental disorders, including Alzheimer’s disease and Gaucher disease have also been shown to have peripheral plasmalogen deficiencies. We previously generated a Pex7 knockout (KO) mouse that serves as an in vivo model for RCDP type 1 , and shows all the biochemical and pathological characteristics of RCDP. Using this mouse model we showed that a diet enriched with 1-O-octadecyl-rac-glycerol, an alkyl-glycerol (AG), can restore plasmalogen levels and rescue the pathology caused by the plasmalogen deficiency. Plasmalogen levels were restored in most tissues examined and the pathological progress of the disorder was halted. When given prior to the occurrence of pathological changes, the AG-di...
Rapid synthesis and turnover of brain microsomal ether phospholipids in the adult rat
Journal of lipid research, 2002
The rates of synthesis, turnover, and half-lives were determined for brain microsomal ether phospholipids in the awake adult unanesthetized rat. A multicompartmental kinetic model of phospholipid metabolism, based on known pathways of synthesis, was applied to data generated by a 5 min intravenous infusion of [1,1-(3)H]hexadecanol. At 2 h post-infusion, 29%, 33%, and 31% of the total labeled brain phospholipid was found in the 1-O-alkyl-2-acyl-sn-glycero-3-phosphate, ethanolamine, and choline ether phospholipid fractions, respectively. Autoradiography and membrane fractionation showed that 3% of the net incorporated radiotracer was in myelin at 2 h, compared to 97% in gray matter microsomal and synaptosomal fractions. Based on evidence that ether phospholipid synthesis occurs in the microsomal membrane fraction, we calculated the synthesis rates of plasmanylcholine, plasmanylethanolamine, plasmenylethanolamine, and plasmenylcholine equal to 1.2, 9.3, 27.6, and 21.5 nmol. g(-1). min(...
Journal of neurochemistry, 2016
Epoxyeicosatrienoic acids (EETs) are synthesized in astrocytes, and inhibitors of soluble epoxide hydrolase (sEH), which hydrolyzes EETs, reduce infarct volume in ischemic stroke. Astrocytes can release protective neurotrophic factors, such as vascular endothelial growth factor (VEGF). We found that addition of sEH inhibitors to rat cultured astrocytes immediately after oxygen-glucose deprivation (OGD) markedly increased VEGF concentration in the medium 48 h later and the effect was blocked by an EET antagonist. The sEH inhibitors increased EET concentrations to levels capable of increasing VEGF. When the sEH inhibitors were removed from the medium at 48 h, the increase in VEGF persisted for an additional 48 h. Neurons exposed to OGD and subsequently to astrocyte medium previously conditioned with OGD plus sEH inhibitors showed increased phosphorylation of their VEGF receptor-2, less TUNEL staining, and increased phosphorylation of Akt, which was blocked by a VEGF receptor-2 antagon...
Endothelial dysfunction in neuroprogressive disorders—causes and suggested treatments
BMC Medicine
Background Potential routes whereby systemic inflammation, oxidative stress and mitochondrial dysfunction may drive the development of endothelial dysfunction and atherosclerosis, even in an environment of low cholesterol, are examined. Main text Key molecular players involved in the regulation of endothelial cell function are described, including PECAM-1, VE-cadherin, VEGFRs, SFK, Rho GEF TRIO, RAC-1, ITAM, SHP-2, MAPK/ERK, STAT-3, NF-κB, PI3K/AKT, eNOS, nitric oxide, miRNAs, KLF-4 and KLF-2. The key roles of platelet activation, xanthene oxidase and myeloperoxidase in the genesis of endothelial cell dysfunction and activation are detailed. The following roles of circulating reactive oxygen species (ROS), reactive nitrogen species and pro-inflammatory cytokines in the development of endothelial cell dysfunction are then described: paracrine signalling by circulating hydrogen peroxide, inhibition of eNOS and increased levels of mitochondrial ROS, including compromised mitochondrial ...