Adipocytic Differentiation and Liver X Receptor Pathways Regulate the Accumulation of Triacylglycerols in Human Vascular Smooth Muscle Cells

Davies, John Dwyfor; Carpenter, Keri L. H.; Challis, Iain R.; Figg, N.; McNair, Rosamund; Proudfoot, Diane; Weissberg, Peter L.; Shanahan, Catherine M.

doi:10.1074/jbc.m410075200

Cited by 75 publications

(73 citation statements)

References 89 publications

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“…67 Further implications for the influence of leptin on lipid-laden foam cell formation come from observations that vascular smooth muscle cells treated with an adipocyte differentiation medium accumulate lipids and express both leptin and leptin receptor ObRb. 68 Leptin's induction of neutral lipid accumulation is in agreement with work showing that leptin increases cholesterol ester storage in a mouse macrophage cell line. 69 Accordingly, insulin-driven mTOR activation leads to adipocyte differentiation and increased lipid storage, accompanied by the induction of fatty acid synthase and PPARγ.…”

Section: Leptin and Mtor: Partners In Macrophage Metabolism And Activsupporting

confidence: 74%

Leptin and mTOR: Partners in metabolism and inflammation

Maya‐Monteiro¹,

Bozza²

2008

Cell Cycle

101

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Section: Leptin and Mtor: Partners In Macrophage Metabolism And Activsupporting

confidence: 74%

Leptin and mTOR: Partners in metabolism and inflammation

Maya‐Monteiro¹,

Bozza²

2008

Cell Cycle

101

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“…Recently, Davies et al did not find perilipin mRNA, or extremely low levels, in SMCs from human arterial wall. 25 Taken together, these results suggest that robust expression of perilipin occurs, at least in macrophages and SMC, only during massive and prolonged cholesterol loading, contrary to ADRP that is expressed in macrophages even before cholesterol loading. 15,16 This would be consistent with the expression pattern of ADRP and perilipin in adipocytes: ADRP is expressed early during the differentiation of adipocytes and the initial constitution of small lipid droplets, whereas perilipin is expressed later in fully differentiated adipocytes with large lipid droplets.…”

Section: Discussionmentioning

confidence: 64%

Genes of Cholesterol Metabolism in Human Atheroma

Forcheron

Legedz

Chinetti-Gbaguidi

et al. 2005

ATVB

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Objective-Accumulation of cholesterol in foam cells of atheroma plaques depends on the balance between uptake and efflux of cholesterol. It may also depend on proteins surrounding lipid droplets, adipophilin, and perilipins. They favor triglyceride storage in adipocytes and could play a similar role for cholesterol in atheroma. Methods and Results-We measured in human atheroma and nearby macroscopically intact tissue (MIT) the expression of perilipin, adipophilin, and regulatory factors of cholesterol metabolism. We identified perilipin A in human arterial wall. Its expression was largely increased in atheroma compared with MIT, and perilipin was present in macrophages and vascular smooth muscle cells. Adipophilin, ACAT1, and CD36 were also overexpressed in atheroma. mRNA levels of low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and SREBP-2 were unchanged. With respect to efflux of cholesterol, the mRNA levels of NCEH and ABCA-1 were unchanged, whereas CLA-1 mRNA was slightly higher in atheroma. Importantly, immunoblotting of ABCA-1 showed a dramatic decrease of ABCA1 protein, the key molecule of cholesterol efflux, in atheroma compared with MIT. Conclusion-We

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“…In atherosclerosis, VSMC have the ability to undergo reversible differentiation into cells with features of other mesenchymal lineages, such as osteoblasts, chondrocytes, and adipocytes (15,57,58). We found that H 2 O 2 -induced VSMC calcification was associated with down-regulation of VSMC-specific markers and induction of bone markers, including ALP, OC, and Col I (Fig.…”

Section: Discussionmentioning

confidence: 71%

Oxidative Stress Induces Vascular Calcification through Modulation of the Osteogenic Transcription Factor Runx2 by AKT Signaling

Byon

Javed

Dai

et al. 2008

Journal of Biological Chemistry

556

537

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Oxidative stress plays a critical role in the pathogenesis of atherosclerosis including the formation of lipid laden macrophages and the development of inflammation. However, oxidative stress-induced molecular signaling that regulates the development of vascular calcification has not been investigated in depth. Osteogenic differentiation of vascular smooth muscle cells (VSMC) is critical in the development of calcification in atherosclerotic lesions. An important contributor to oxidative stress in atherosclerotic lesions is the formation of hydrogen peroxide from diverse sources in vascular cells. In this study we defined molecular signaling that is operative in the H 2 O 2 -induced VSMC calcification. We found that H 2 O 2 promotes a phenotypic switch of VSMC from contractile to osteogenic phenotype. This response was associated with an increased expression and transactivity of Runx2, a key transcription factor for osteogenic differentiation. The essential role of Runx2 in oxidative stress-induced VSMC calcification was further confirmed by Runx2 depletion and overexpression. Inhibition of Runx2 using short hairpin RNA blocked VSMC calcification, and adenovirus-mediated overexpression of Runx2 alone induced VSMC calcification. Inhibition of H 2 O 2 -activated AKT signaling blocked VSMC calcification and Runx2 induction concurrently. This blockage did not cause VSMC apoptosis. Taken together, our data demonstrate a critical role for AKT-mediated induction of Runx2 in oxidative stress-induced VSMC calcification.Atherosclerosis is characterized by the presence of atherosclerotic lesions in the arterial intima that leads to narrowing of the vessel lumen. Vascular calcification, the presence of calcium deposits in the vessel wall, is a feature of advanced atherosclerosis and reduces elasticity and compliance of the vessel wall (1). Hence, the extent of calcification is a key risk factor in the pathogenesis of the disease. Several cell types, such as endothelium, monocytes, and vascular smooth muscle cells (VSMC), 5 are involved in different stages of lesion development. VSMC contribute to the development of atherosclerotic lesions through increased migration, proliferation, secretion of matrix components, osteogenic differentiation, and the associated calcification (1). During this process, the differentiated VSMC undergo de-differentiation, and subsequently osteogenic transition that results in vascular calcification (2).Many factors that have been linked to an increased prevalence of vascular calcification are associated with elevated oxidative stress, including hypercholesterolemia, hypertension, diabetes mellitus, and dialysis-dependent end stage renal disease (3-6). Pro-oxidant events in atherosclerosis include the production of reactive oxygen species (ROS) and nitrogen species by vascular cells (7). Of particular interest is hydrogen peroxide (H 2 O 2 ), which is a cell-permeable ROS that has emerged as a key mediator of intracellular signaling (8 -10). H 2 O 2 is produced in vascular cells by multiple enzyma...

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Adipocytic Differentiation and Liver X Receptor Pathways Regulate the Accumulation of Triacylglycerols in Human Vascular Smooth Muscle Cells

Cited by 75 publications

References 89 publications

Leptin and mTOR: Partners in metabolism and inflammation

Leptin and mTOR: Partners in metabolism and inflammation

Genes of Cholesterol Metabolism in Human Atheroma

Oxidative Stress Induces Vascular Calcification through Modulation of the Osteogenic Transcription Factor Runx2 by AKT Signaling

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