Cyclodextrin promotes atherosclerosis regression via LXR activation (I)
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67011 | GEO | 2016/05/06
SECONDARY ACCESSION(S): PRJNA278710
REPOSITORIES: GEO
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Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis 1, cardiovascular disease remains the leading cause of death worldwide 2. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response 3 4, we tested the therapeutic potential of increasing cholesterol solubility in experimental atherogenesis. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal load and promoted plaque regression even under continuing Western diet. CD solubilized CCs and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor (LXR)-mediated transcriptional reprogramming. CD increased cholesterol efflux from macrophages and substantially augmented reverse cholesterol transport in vivo. Furthermore, CD reduced proinflammatory cytokines in vivo and decreased macrophage responsiveness towards TLR and inflammasome activation. Since CD treatment in humans is safe and CD beneficially affects key pathogenetic factors in atherogenesis it may thus be used clinically to prevent or treat human atherosclerosis .
2016-05-06 | GSE67013 | GEO
Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Since cholesterol retention and cholesterol crystals in arterial walls are key pathogenetic factors for atherogenesis, we assessed the therapeutic potential of increasing cholesterol solubility in vivo. Here we show that treatment of murine atherosclerosis with the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that solubilizes lipophilic substances, reduced atherosclerotic plaque size, cholesterol crystal (CC) load and promoted plaque regression even under continuing Western diet. CD solubilized CC and promoted cholesterylester and oxysterol production in macrophages leading to liver X receptor-mediated transcriptional reprogramming with increased cholesterol efflux and decreased inflammation. CD treatment may thus be used to increase cholesterol solubility and clearance to prevent or treat atherosclerosis.
2017-07-01 | GSE47696 | GEO
Project description:Objective: Although relationships between smoking and cardiovascular diseases (CVD), and CVD and lipids are established, direct impact of cigarette smoke (CS) on lipidomes remains elusive. We investigated the effect of 6 month smoke exposure on a well-established mouse model for human atherogenesis, Apoe mouse plasma, liver, and aorta molecular lipid profiles and liver transcriptome. // Methods: Plasma, liver, and aorta samples from Apoe mice exposed to CS or fresh air for 6 months were extracted for lipids using robotic-assisted method and analyzed by mass spectrometry. Gene expression of samples from the same livers was obtained on microarrays. Development of atherosclerosis in aorta was further assessed by plaque size measurement in the aortic arch and lipoprotein measurements in plasma and in the plaque. // Results: CS increased most lipid classes and molecular lipid species in tissues evaluated. In plasma, free cholesterol, ceramides, cerebrosides, and majority of phospholipids were increased in CS-exposed mice. In liver, CS elevated several lipid species including free and esterified cholesterol, triacylglycerols, phospholipids, sphingomyelins, and ceramides. In aorta, more than 2-fold higher cholesteryl ester (CE), lysophosphatidylcholine, and glucosyl/galactosylceramide levels were recorded in mice exposed to CS compared to mice exposed to fresh air. Moreover, CS exposure induced a significant decrease in several plasma CE and phosphatidylcholine species that contained polyunsaturated fatty acids. Genes involved in amino acid and lipid metabolism showed perturbed transcription profiles in liver. // Conclusion: These data reveal molecular details accompanying the increase in plaque size, sign of atherogenesis in Apoe mice, which is accelerated by CS exposure.
2013-10-03 | E-MTAB-1195 | biostudies-arrayexpress
Project description:miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33–knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.
2021-02-11 | PXD023471 | Pride
Project description:Cholesterol biosynthetic intermediates such as lanosterol and desmosterol are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon (IFN) responses and attenuates the expression of anti-inflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/RXR activation and thus, macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mito-ROS production and NLRP3-dependent inflammasome activation. Deficiency of NLRP3 or ASC rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation, by integrating with macrophage cholesterol metabolism and inflammatory activation, and protecting from disease progression.
2021-12-01 | GSE175312 | GEO
Project description:Cholesterol biosynthetic intermediates such as lanosterol and desmosterol are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon (IFN) responses and attenuates the expression of anti-inflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/RXR activation and thus, macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mito-ROS production and NLRP3-dependent inflammasome activation. Deficiency of NLRP3 or ASC rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation, by integrating with macrophage cholesterol metabolism and inflammatory activation, and protecting from disease progression.
2021-12-31 | GSE172374 | GEO
Project description:Background: It is recognized that atherosclerosis can regresses at least in animal models. However, little is known about the mechanisms. We induced regression of advanced atherosclerosis in apolipoprotein E deficient (APOE/) mice and studied underlying mechanisms. Unexpectedly, our study led to the role of interleukin-7 (IL-7) in atherogenesis. Methods and Results: We treated APOE/ mice fed a high cholesterol diet for 30 weeks to induce advanced lesions with a helper-dependent adenoviral vector expressing human apoE3 (HDAd-gE3), and analyzed the regression of atherosclerosis after 41 weeks. Using microarray analysis, we identified IL-7 as one of most significantly affected genes by lowering cholesterol. To answer why IL-7 is downregulated by reduced cholesterol, we studied effects of IL-7 on endothelial cells (ECs). Our major findings were (1) long-term lowering cholesterol induced regression of advanced atherosclerosis. (2) Microarray analysis identified multiple signaling pathways affected by lowering cholesterol. (3) Correction for multiple testing revealed that IL-7 expression was downregulated, whereas gamma-sarcoglycan and α-actin were upregulated. (4) Oxidized LDL upregulated IL-7 expression in macrophages but not in aorta ECs or smooth muscle cells. (5) IL-7 increased the expression of cell adhesion molecules and chemokine in ECs and promoted monocyte adhesion to ECs. (6) Systemic elevation of IL-7 induced inflammatory response and recruited monocyte/macrophage to the lesions without increasing plasma cholesterol. Conclusion: Our finding suggest that IL-7 inflames endothelium and triggers the adhesion/recruitment of monocyte/macrophages to the atherosclerotic lesions and thus plays a direct role in development of atherosclerosis. Key Words: arteriosclerosis, gene therapy, hypercholesterolemia, interleukins, cell adhesion molecules Female APOE-/- mice (8 weeks of age) on a C57BL/6 background were purchased from Jackson Laboratory and were fed a diet containing 0.2% (w/w) cholesterol and 10% (v/w) coconut oil to induce atherosclerosis for 30 weeks. Mice were then divided into 3 groups, (n=15/group), treated with a tail vein injection of helper-dependent adenovirus expressing human apolipoprotein E3 (HDAd-gE3, 5 x 1012 viral particles/kg, n=11, vector), empty vector (HDAd-0, 5 x 1012 VP/kg, n=11, vector control) or phosphate buffered saline (PBS, vehicle) and sacrificed 10 days after. Three aortas extending sinus to arch were pooled for RNA extraction with an RNeasy kit (Qiagen). Sample ID 12031: E4: vector control (HDAd-0) 12043: E5: vector control 12046: V2: vector 12047: V3: vector 12048: V4: vector 12051: B1: vehicle (PBS) 12053: B3: vehicle 12054: B4: vehicle 12039: E3: vector control
2009-10-01 | E-GEOD-15914 | biostudies-arrayexpress
Project description:Background: It is recognized that atherosclerosis can regresses at least in animal models. However, little is known about the mechanisms. We induced regression of advanced atherosclerosis in apolipoprotein E deficient (APOE/) mice and studied underlying mechanisms. Unexpectedly, our study led to the role of interleukin-7 (IL-7) in atherogenesis. Methods and Results: We treated APOE/ mice fed a high cholesterol diet for 30 weeks to induce advanced lesions with a helper-dependent adenoviral vector expressing human apoE3 (HDAd-gE3), and analyzed the regression of atherosclerosis after 41 weeks. Using microarray analysis, we identified IL-7 as one of most significantly affected genes by lowering cholesterol. To answer why IL-7 is downregulated by reduced cholesterol, we studied effects of IL-7 on endothelial cells (ECs). Our major findings were (1) long-term lowering cholesterol induced regression of advanced atherosclerosis. (2) Microarray analysis identified multiple signaling pathways affected by lowering cholesterol. (3) Correction for multiple testing revealed that IL-7 expression was downregulated, whereas gamma-sarcoglycan and α-actin were upregulated. (4) Oxidized LDL upregulated IL-7 expression in macrophages but not in aorta ECs or smooth muscle cells. (5) IL-7 increased the expression of cell adhesion molecules and chemokine in ECs and promoted monocyte adhesion to ECs. (6) Systemic elevation of IL-7 induced inflammatory response and recruited monocyte/macrophage to the lesions without increasing plasma cholesterol. Conclusion: Our finding suggest that IL-7 inflames endothelium and triggers the adhesion/recruitment of monocyte/macrophages to the atherosclerotic lesions and thus plays a direct role in development of atherosclerosis. Key Words: arteriosclerosis, gene therapy, hypercholesterolemia, interleukins, cell adhesion molecules
2009-10-01 | GSE15914 | GEO
Project description:Currently, no mouse models manifest calcification and thrombus formation, which is frequently associated with human atherosclerosis. We demonstrated that lack of Favine/CCDC3 in apoE knockout mice accelerated atherosclerosis accompanied by large cholesterol crystals and calcification, and also promoted thrombus formation in the left ventricle and arteries. Circulating Favine was detectable in WT mouse lasma. RNA-sequencing analysis of aortae in DKO mice showed similar gene expression patterns of human atherosclerosis with unstable and vulnerable plaques. Importantly, human FAVINE mRNA expressions were lower in atheroma plaque than in adjacent intact aortic tissue and decreased with the progression of atherosclerosis. Pathway analysis of aortae in DKO mice suggested the decrease of the MEF2C-KLF2-mediated transcriptional pathway. Favine insufficiency and its attenuated downstream pathways may increase atherosclerosis progression with calcification and thrombus, which have not previously been fully modeled in experimental animals. Favine and its downstream pathways may have therapeutic potential for atherosclerosis.
2022-10-12 | GSE183376 | GEO
Project description:miR-33 is an intronic miRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve HDL biogenesis in the liver and increase circulating HDL-C levels in both rodents and non-human primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole body miR-33 knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver, and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardio-metabolic diseases.
2021-01-31 | GSE164517 | GEO