Lack of apoA-I in apoEKO mice causes skin xanthomas, worsening of inflammation and increased coronary atherosclerosis in the absence of hyperlipidemia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE202237 | GEO | 2022/05/07
REPOSITORIES: GEO
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Project description:HDL particles are known to possess several anti-atherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant and antiinflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments. Methods Eight weeks old EKO mice, EKO mice overexpressing human apoA-I (EKO/hA-I) and wild-type mice as controls were fed either Chow or Western diet for 6 or 22 weeks. Cholesterol distribution among lipoproteins was evaluated and atherosclerosis of the aorta was quantified. High-throughput sequencing technologies were used to analyse the transcriptome of the aorta of the three genotypes in each experimental condition. Results: In addition to the well-known activation of inflammation and immune response, the impairment of sphingolipid metabolism, phagosome-lysosome system and osteoclast differentiation emerged as relevant players in atherosclerosis development. The reduced atherosclerotic burden in the aorta of EKO mice expressing high levels of apoA-I was accompanied by a reduced activation of the immune system markers, as well as reduced perturbation of lysosomal activity and a better regulation of the sphingolipid synthesis pathway Conclusions. ApoA-I modulates atherosclerosis development in the aorta of EKO mice affecting the expression of pathways additional to those associated with inflammation and immune response
2020-12-22 | GSE163657 | GEO
Project description:Specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis. Carriers do not exhibit increased cardiovascular disease risk despite reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of L75P and L174S patients presents a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.
2020-11-20 | PXD021266 | Pride
Project description:Purpose: To clarify cellular and molecular mechanisms underlying impaired post-ischemic adaptive vascular responses and to evaluate reconstituted HDL (rHDL)-ApoA-I nanotherapy to rescue the defect in type 2 diabetic (T2DM) mouse model of hindlimb ischemia (HLI). Methods: Mice with beta-cell specific over-expression of insulin-like growth factor-2 in atherosclerotic background (IGF-II/ LDLR-/-ApoB100/100) with T2DM features were used in the study with C57BL/6J mice fed with a regular chow-diet (R36, Lactamin) serving as controls. Mice aged between 16 to 20 weeks were used in the study . Mice were anaesthetized with 1.5-2% isoflurane/air mixture during the surgical procedure. Hair was removed from the operation site and cleaned with sterile water. Single incision was made just above medial thigh and superficial femoral artery was separated from femoral vein and nerve. HLI was induced by unilateral ligation of femoral artery distal to the origin of the profunda femoral artery. The skin was closed with interrupted silk sutures. Mice were were administered with reconstituted ApoA-I nanoparticles with phosphatidyl serine core (rHDL) intravenously starting 2 days post-HLI with doses every 2 days until scarification with Saline injections serving as controls. Adductors muscle aortic endothelial cells (AECs) and Ischemic muscle Macrophages and Endothelial Cells (ECs) were isolated using a combination of magnetic assisted cell sorting and flow Cytometry using Macrophage (F4/80) and EC (CD-31) specific markers. Total RNA isolated from FACS sorted cells were used for RNA seq library preparation. Results: Cell-specific gene expression, flow cytometry and immunohistochemistry revealed a persistent Macrophage and Endothelial cell inflammation and a reduced anti-inflammatory M2-macrophage activation associated with impaired collateral remodelling and sprouting angiogenesis in T2DM mice. Furthermore, reconstituted HDL (rHDL)- ApoA-I was found to rescue impaired collateral remodelling and angiogenesis in T2DM mice through modulating EC and macrophage phenotypes. Conclusions: Our results suggest that an impaired collateral remodelling and sprouting angiogenesis in T2DM mice after HLI is associated with a persistent EC and macrophage inflammation and a reduced activation of anti-inflammatory M2-macrophage. Skewing the macrophage phenotype towards the pro-arteriogenic and pro-angiogenic anti-inflammatory M2-macrophages using reconstituted HDL (rHDL)-ApoA-I nanotherapy may serve as a potential therapeutic modality for T2DM PAD.
2023-01-30 | GSE197392 | GEO
Project description:BackgroundHDL (high-density lipoprotein) and its major protein component, apoA-I (apolipoprotein A-I), play a unique role in cholesterol homeostasis and immunity. ApoA-I deficiency in hyperlipidemic, atheroprone mice was shown to drive cholesterol accumulation and inflammatory cell activation/proliferation. The present study was aimed at investigating the impact of apoA-I deficiency on lipid deposition and local/systemic inflammation in normolipidemic conditions.MethodsApoE deficient mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I, and C57Bl/6J control mice were fed normal laboratory diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric, and whole transcriptome analyses.ResultsDKO were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to control mice. Only DKO showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4+ T effector memory cells was detected in blood, spleen, and skin-draining lymph nodes of DKO. A worsening of atherosclerosis at the aortic sinus and coronary arteries was also observed in DKO versus apoE deficient. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and halt atherosclerosis development.ConclusionsHDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, aortic and coronary atherosclerosis, local and systemic inflammation.
| S-EPMC9205301 | biostudies-literature
Project description:Lack of apoA-I in apoEKO mice causes skin xanthomas, worsening of inflammation and increased coronary atherosclerosis in the absence of hyperlipidemia
| PRJNA835106 | ENA
Project description:We found ApoA-I from blood can be taken up by microglia in the brain. To determine if ApoA-I from circulation is sufficient to restore microglial transcriptomic state to a more wild-type-like state, we performed a rescue experiment by intravenously injecting ApoA-I protein into adult Apoa1 KO mice and sorted microglia with or without ApoA-I uptake for bulk transcriptomic analysis.
2024-10-15 | GSE264111 | GEO
Project description:Apolipoprotein A-I is well known to play a role in cholesterol efflux, but our studies suggest that apoA-I may also induce proinflammatory signaling. The molecular mechanisms behind apoA-I-mediated proinflammatory signaling have not yet been explored, nor has the link between this signaling and cholesterol efflux. We hypothesize that apoA-I is a novel TLR agonist, signaling through the MyD88 proinflammatory signaling adaptor to induce cytokines. Microarray analysis confirmed that a suite of pro-inflammatory genes are induced by apoA-I with varying dependence upon MyD88, and that MyD88 regulates >6% of the apoA-I-induced transcriptome.
2010-06-15 | GSE13772 | GEO
Project description:To test the functional role of ApoA-I on microglia in the context of stress, we treated primary microglia with LPS stress with or without ApoA-I protein, and used bulk RNA-seq to evaluate if ApoA-I exhibits an anti-inflammatory role.
2024-10-15 | GSE264110 | GEO
Project description:Apolipoprotein A-I (apoA-I) is cross-linked and dysfunctional in human atheroma. Although multiple mechanisms of apoA-1 cross-linking have been demonstrated in vitro, the in vivo mechanisms of cross-linking are not well established. We have recently demonstrated the highly selective and efficient modification of high-density lipoprotein (HDL) apoproteins by endogenous oxidized phospholipids (oxPLs), including oxoalkenal phospholipids. In the current study, we report that oxoalkenal phospholipids effectively cross-link apoproteins in HDL. We further demonstrate that cross-linking impairs the cholesterol efflux mediated by apoA-I or HDL3 in vitro and in vivo. Using LC-MS/MS analysis, we analyzed the pattern of apoprotein cross-linking in isolated human HDL either by synthetic oxoalkenal phospholipids or by oxPL generated during HDL oxidation in plasma by the physiologically relevant MPO-H2O2-NO2- system. We found that five histidine residues in helices 5-8 of apoA-I are preferably cross-linked by oxPL, forming stable pyrrole adducts with lysine residues in the helices 3-4 of another apoA-I or in the central domain of apoA-II. We also identified cross-links of apoA-I and apoA-II with two minor HDL apoproteins, apoA-IV and apoE. We detected a similar pattern of apoprotein cross-linking in oxidized murine HDL. We further detected oxPL cross-link adducts of HDL apoproteins in plasma and aorta of hyperlipidemic LDLR-/- mice, including cross-link adducts of apoA-I His-165--apoA-I Lys-93, apoA-I His-154--apoA-I Lys-105, apoA-I His-154--apoA-IV Lys-149, and apoA-II Lys-30/apoE His-227. These findings suggest an important mechanism that contributes to the loss of HDL's atheroprotective function in vivo.
2019-12-13 | MSV000084689 | MassIVE
Project description:ApoA-1 and Atherosclerosis in Psoriasis
| PRJNA946881 | ENA