GW27-e0102 miR-98 Regulates Endothelial Dysfunction, Foam Cell Formation and Lipid Accumulation in ApoE-/- Mice Aorta Through Repression of LOX-1

Background: Synthetic forms of glucocorticoids (GCs; eg, prednisone, prednisolone) are anti-inflammatory drugs that are widely used in clinical practice. The role of GCs in cardiovascular diseases, including atherosclerosis, is highly controversial, and their impact on macrophage foam cell formation is still unknown. We investigated the effects of prednisone and prednisolone on macrophage oxidative stress and lipid metabolism. Methods and Results: C57BL/6 mice were intraperitoneally injected with prednisone or prednisolone (5 mg/kg) for 4 weeks, followed by lipid metabolism analyses in the aorta and peritoneal macrophages. We also analyzed the effect of serum samples obtained from 9 healthy human volunteers before and after oral administration of prednisone (20 mg for 5 days) on J774A.1 macrophage atherogenicity. Finally, J774A.1 macrophages, human monocyte-derived macrophages, and fibroblasts were incubated with increasing concentrations (0-200 ng/mL) of prednisone or prednisolone, followed by determination of cellular oxidative status, and triglyceride and cholesterol metabolism. Prednisone and prednisolone treatment resulted in a significant reduction in triglyceride and cholesterol accumulation in macrophages, as observed in vivo, ex vivo, and in vitro. These effects were associated with GCs’ inhibitory effect on triglyceride- and cholesterol-biosynthesis rates, through downregulation of diacylglycerol acyltransferase 1 and HMG-CoA reductase expression. Glucocorticoid-induced reduction of cellular lipid accumulation was mediated by the GC receptors on the macrophages, because the GC-receptor antagonist (RU486) abolished these effects. In fibroblasts, unlike macrophages, GCs showed no effects. Conclusion: Prednisone and prednisolone exhibit antiatherogenic activity by protecting macrophages from lipid accumulation and foam cell formation.

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Effects of diosgenin and its derivatives on atherosclerosis

Food & Function ◽

10.1039/c9fo00749k ◽

2019 ◽

Vol 10 (11) ◽

pp. 7022-7036 ◽

Cited By ~ 10

Author(s):

Fang-Chun Wu ◽

Jian-Guo Jiang

Keyword(s):

Endothelial Dysfunction ◽

Lipid Profile ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Macrophage Foam Cell

The effects of diosgenin are discussed with respect to endothelial dysfunction, lipid profile, macrophage foam cell formation, VSMC viability, thrombosis and inflammation during the formation of atherosclerosis.

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Smooth Muscle Cell Foam Cell Formation, Apolipoproteins, and ABCA1 in Intracranial Aneurysms: Implications for Lipid Accumulation as a Promoter of Aneurysm Wall Rupture

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlw041 ◽

2016 ◽

Vol 75 (7) ◽

pp. 689-699 ◽

Cited By ~ 34

Author(s):

Eliisa Ollikainen ◽

Riikka Tulamo ◽

Satu Lehti ◽

Miriam Lee-Rueckert ◽

Juha Hernesniemi ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Lipid Accumulation ◽

Intracranial Aneurysms ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Aneurysm Wall ◽

Cell Foam

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Abstract 570: Macrophage Catabolism of Aggregated Lipoproteins Using a Novel Extracellular Compartment Regulates Lipid Accumulation During Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.570 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Rajesh K Singh ◽

Abigail S Haka ◽

Valeria C Barbosa-Lorenzi ◽

Arky Asmal ◽

Frederik Lund ◽

...

Keyword(s):

Lipid Accumulation ◽

Actin Polymerization ◽

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Atherosclerotic Vascular Disease ◽

Extracellular Compartment

Despite impressive advances in research, prevention, and treatment, atherosclerotic vascular disease remains the leading cause of death in the developed world. Mechanisms of cholesterol accumulation in the arteries have been studied intensively, but the in vivo contributions of different pathways leading to lipid accumulation and foam cell formation are not understood. In the arteries, low-density lipoprotein (LDL) is aggregated and bound to the extracellular matrix. When such aggregated LDL is presented to macrophages, they form a novel acidic, hydrolytic compartment that is topologically extracellular, to which lysosomal enzymes are secreted. Such compartments are observed in vivo in murine atherosclerotic plaque macrophages interacting with cholesterol rich deposits. Using state-of-the-art quantitative and high resolution microscopy techniques, characterization of compartment morphology reveals how macrophages use local actin polymerization to drive plasma membrane remodeling at the interface with aggregated LDL. This leads to sequestration of aggregated LDL into topologically convoluted structures that allow acidification, catabolism and internalization of LDL. We find that a TLR4/MyD88/Syk/PI3 kinase/Akt dependent signaling pathway in macrophages regulates the formation of such catabolic compartments. Consistent with this, deficiency of TLR4 in vivo can protect macrophages from lipid accumulation in murine atherosclerotic plaques. Herein, we provide compelling evidence for a novel form of catabolism that macrophages use to degrade aggregated LDL in vivo during atherosclerosis and this process leads to foam cell formation, cell death and promotes disease progression.

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2-Aminopurine Inhibits Lipid Accumulation Induced by Apolipoprotein E-Deficient Lipoprotein in Macrophages: Potential Role of Eukaryotic Initiation Factor-2α Phosphorylation in Foam Cell Formation

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.107.134833 ◽

2008 ◽

Vol 326 (2) ◽

pp. 395-405 ◽

Cited By ~ 2

Author(s):

DongFang Wu ◽

Hong Yang ◽

YanFeng Zhao ◽

Chakradhari Sharan ◽

J. Shawn Goodwin ◽

...

Keyword(s):

Apolipoprotein E ◽

Lipid Accumulation ◽

Potential Role ◽

Foam Cell ◽

Cell Formation ◽

Initiation Factor ◽

Foam Cell Formation ◽

Eukaryotic Initiation Factor

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Advanced glycation end products (AGEs) increase human mesangial foam cell formation by increasing Golgi SCAP glycosylation in vitro

AJP Renal Physiology ◽

10.1152/ajprenal.00646.2010 ◽

2011 ◽

Vol 301 (1) ◽

pp. F236-F243 ◽

Cited By ~ 22

Author(s):

Yang Yuan ◽

Lei Zhao ◽

Yaxi Chen ◽

John F. Moorhead ◽

Zac Varghese ◽

...

Keyword(s):

Advanced Glycation End Products ◽

Lipid Accumulation ◽

Foam Cell ◽

Cell Formation ◽

Protein Glycosylation ◽

Foam Cell Formation ◽

Advanced Glycation ◽

Processing Enzymes ◽

Glycation End Products ◽

End Products

Advanced glycation end products (AGEs) is one of the causative factors of diabetic nephropathy, which is associated with lipid accumulation in glomeruli. This study was designed to investigate whether Nε-(carboxymethyl) lysine (CML; a member of the AGEs family) increases lipid accumulation by impairing the function of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) in human mesangial cells (HMCs). Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The activity of Golgi-processing enzymes was determined using enzyme-based methods, and the translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. CML increased cholesterol accumulation in HMCs. Exposure to CML increased expression and abnormal translocation of SCAP from the ER to the Golgi even in the presence of a high concentration of LDL. The increased SCAP translocation carried more SREBP-2 to the Golgi for activation by proteolytic cleavages, enhancing transcription of 3-hydroxy-3-methylclutaryl-CoA reductase and the LDL receptor. CML increased Golgi mannosidase activity, which may enhance glycosylation of SCAP. This prolonged the half-life and enhanced recycling of SCAP between the ER and the Golgi. The effects of CML were blocked by inhibitors of Golgi mannosidases. AGEs (CML) increased lipid synthesis and uptake, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in HMCs. These data imply that inhibitors of Golgi-processing enzymes might have a potential renoprotective role in prevention of mesangial foam cell formation.

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Lipopolysaccharide stimulation of RAW 264.7 macrophages induces lipid accumulation and foam cell formation

Atherosclerosis ◽

10.1016/0021-9150(93)90224-i ◽

1993 ◽

Vol 98 (1) ◽

pp. 67-82 ◽

Cited By ~ 108

Author(s):

Janet L. Funk ◽

Kenneth R. Feingold ◽

Arthur H. Moser ◽

Carl Grunfeld

Keyword(s):

Lipid Accumulation ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Raw 264.7 ◽

Raw 264.7 Macrophages ◽

Stimulation Of

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TLR4-dependent signaling drives extracellular catabolism of low-density lipoprotein aggregates

10.1101/610162 ◽

2019 ◽

Author(s):

Rajesh K. Singh ◽

Abigail S. Haka ◽

Arky Asmal ◽

Valéria C. Barbosa-Lorenzi ◽

Inna Grosheva ◽

...

Keyword(s):

Bone Marrow ◽

Knockout Mice ◽

Lipid Accumulation ◽

Foam Cell ◽

Cell Formation ◽

Adaptor Protein ◽

Foam Cell Formation ◽

Low Density

ABSTRACTObjectiveAggregation and modification of low-density lipoproteins (LDL) promotes their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of aggregated LDL (agLDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse (LS). Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites such as cholesterol promotes foam cell formation, a process that drives atherogenesis. Further, there is accumulating evidence for the involvement of TLR4 and its adaptor protein MyD88 in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the LS and foam cell formation.Approach and ResultsUsing bone marrow-derived macrophages (BMMs) from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment and foam cell formation. Using siRNA, pharmacological inhibition and knockout BMMs, we implicate SYK, PI3 kinase and Akt in agLDL catabolism using the LS. Using bone marrow transplantation of LDL receptor knockout mice with TLR4KO bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL.ConclusionsWe present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the LS, catabolism of agLDL and lipid accumulation in vitro and in vivo.

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Lack of mitochondrial NADP(H)-transhydrogenase expression in macrophages exacerbates atherosclerosis in hypercholesterolemic mice

Biochemical Journal ◽

10.1042/bcj20190543 ◽

2019 ◽

Vol 476 (24) ◽

pp. 3769-3789 ◽

Cited By ~ 2

Author(s):

Alessandro G. Salerno ◽

Thiago Rentz ◽

Gabriel G. Dorighello ◽

Ana Carolina Marques ◽

Estela Lorza-Gil ◽

...

Keyword(s):

Lipid Accumulation ◽

Double Mutant ◽

Foam Cell ◽

Critical Role ◽

Cell Formation ◽

Ldl Receptor ◽

Liver Mitochondria ◽

Cholesterol Homeostasis ◽

Foam Cell Formation ◽

Wild Type

The atherosclerosis prone LDL receptor knockout mice (Ldlr−/−, C57BL/6J background) carry a deletion of the NADP(H)-transhydrogenase gene (Nnt) encoding the mitochondrial enzyme that catalyzes NADPH synthesis. Here we hypothesize that both increased NADPH consumption (due to increased steroidogenesis) and decreased NADPH generation (due to Nnt deficiency) in Ldlr−/− mice contribute to establish a macrophage oxidative stress and increase atherosclerosis development. Thus, we compared peritoneal macrophages and liver mitochondria from three C57BL/6J mice lines: Ldlr and Nnt double mutant, single Nnt mutant and wild-type. We found increased oxidants production in both mitochondria and macrophages according to a gradient: double mutant > single mutant > wild-type. We also observed a parallel up-regulation of mitochondrial biogenesis (PGC1a, TFAM and respiratory complexes levels) and inflammatory (iNOS, IL6 and IL1b) markers in single and double mutant macrophages. When exposed to modified LDL, the single and double mutant cells exhibited significant increases in lipid accumulation leading to foam cell formation, the hallmark of atherosclerosis. Nnt deficiency cells showed up-regulation of CD36 and down-regulation of ABCA1 transporters what may explain lipid accumulation in macrophages. Finally, Nnt wild-type bone marrow transplantation into LDLr−/− mice resulted in reduced diet-induced atherosclerosis. Therefore, Nnt plays a critical role in the maintenance of macrophage redox, inflammatory and cholesterol homeostasis, which is relevant for delaying the atherogenesis process.

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