Lipoproteins Induce Expression of the Early Growth Response Gene-1 in Vascular Smooth Muscle Cells from Rat

Sachinidis, Agapios; Ko, Yon; Wieczorek, A; Weisser, Burkhard; Locher, Rudolf; Vetter, W; Vetter, Hermann

doi:10.1006/bbrc.1993.1484

Biochemical and Biophysical Research Communications

1993

DOI: 10.1006/bbrc.1993.1484

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Lipoproteins Induce Expression of the Early Growth Response Gene-1 in Vascular Smooth Muscle Cells from Rat

Agapios Sachinidis¹,

Yon Ko²,

A Wieczorek³

et al.

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Cited by 31 publications

(18 citation statements)

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“…[2][3][4][5] Indeed, LDLs induce VSMC mitogenesis, 6 -11 increase intracellular free calcium concentration, 7,9,11 activate mitogen-activated protein kinases (MAPK), 9 -11 and regulate the expression and activity of different transcription factors, including c-fos, egr-1, and sterol regulatory element binding protein-2 (SREBP-2). 9,[12][13][14][15] Recently, we have identified, by mRNA-differential display (mRNA-DD) analysis, neuron-derived orphan receptor-1 (NOR-1) as an early-response gene in VSMCs. 16 NOR-1, together with Nur77 and Nurr1, forms the growth factorinduced protein-B (NGFI-B) family of orphan nuclear receptors within the steroid/thyroid receptor superfamily.…”

mentioning

confidence: 99%

Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB

Rius

Martínez-González

Crespo

et al. 2004

ATVB

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Objective-Low density lipoproteins (LDLs) modulate the expression of key genes involved in atherogenesis. Recently, we have shown that the transcription factor neuron-derived orphan receptor-1 (NOR-1) is involved in vascular smooth muscle cell (VSMC) proliferation. Our aim was to analyze whether NOR-1 is involved in LDL-induced mitogenic effects in VSMC. Methods and Results-LDL induced NOR-1 expression in a time-and dose-dependent manner. Antisense oligonucleotides against NOR-1 inhibit DNA synthesis induced by LDL in VSMCs as efficiently as antisense against the protooncogene c-fos. The upregulation of NOR-1 mRNA levels by LDL involves pertusis-sensitive G protein-coupled receptors, Ca 2ϩ mobilization, protein kinases A (PKA) and C (PKC) activation, and mitogen-activated protein kinase pathways (MAPK) (p44/p42 and p38). LDL promotes cAMP response element binding protein (CREB) activation (phosphorylation in Ser 133 ). In transfection assays a dominant-negative of CREB inhibits NOR-1 promoter activity, while mutation of specific (cAMP response element) CRE sites in the NOR-1 promoter abolishes LDL-induced NOR-1 promoter activity. V ascular smooth muscle cell (VSMC) migration and proliferation play key roles in the pathophysiology of vascular remodeling associated with atherosclerotic diseases. 1,2 Because low density lipoproteins (LDLs) are key factors in the onset and development of atherosclerosis, their effects on VSMCs have been investigated. 2-5 Indeed, LDLs induce VSMC mitogenesis, 6 -11 increase intracellular free calcium concentration, 7,9,11 activate mitogen-activated protein kinases (MAPK), 9 -11 and regulate the expression and activity of different transcription factors, including c-fos, egr-1, and sterol regulatory element binding protein-2 (SREBP-2). 9,[12][13][14][15] Recently, we have identified, by mRNA-differential display (mRNA-DD) analysis, neuron-derived orphan receptor-1 (NOR-1) as an early-response gene in VSMCs. 16 NOR-1, together with Nur77 and Nurr1, forms the growth factorinduced protein-B (NGFI-B) family of orphan nuclear receptors within the steroid/thyroid receptor superfamily. 17 These genes have been involved in neuroendocrine regulation, neural differentiation, liver regeneration, cell apoptosis, and mitogenic stimuli in different cell types. 18 NOR-1 is upregulated by coronary angioplasty, and both NOR-1 and Nur77 are overexpressed in atherosclerotic lesions from patients with coronary artery disease (CAD). 16,19 In the present study, we show that NOR-1 expression is transiently induced by LDL and is linked to LDL-induced VSMC mitogenic effects. NOR-1 induction by LDL involved pertussis-sensitive G protein-coupled receptors, Ca 2ϩ mobilization, the activation of different protein kinases [protein kinases A (PKA) and C (PKC) and MAPK (p44/p42 and p38)], and cAMP response element binding protein (CREB) activation. Finally, analysis of NOR-1 promoter activity revealed a key role of cAMP response elements (CRE) in the upregulation of NOR-1 by LDL. These results suggest that NOR-1 may...

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mentioning

confidence: 99%

Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB

Rius

Martínez-González

Crespo

et al. 2004

ATVB

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show abstract

“…11 In addition to lipid transport, LDL can effectively stimulate SMC proliferation, a key event in the formation of atherosclerosis. [12][13][14] There is evidence that LDL induces gene expression of platelet-derived growth factor (PDGF), PDGF receptors, c-fos, and egr-1, 14,15 which are essential transcription factors for SMC proliferation. However, the precise signal transduction pathways that link to hypercholesterolemia and quantitative changes in gene expression in the pathogenesis of atherosclerotic lesions are largely unknown.…”

mentioning

confidence: 99%

Hyperexpression and Activation of Extracellular Signal–Regulated Kinases (ERK1/2) in Atherosclerotic Lesions of Cholesterol-Fed Rabbits

Dietrich

Metzler

et al. 2000

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Abstract-A hallmark of hyperlipidemia-induced atherosclerosis is altered gene expression that initiates cell proliferation and (de)differentiation in the intima of the arterial wall. The molecular signaling that mediates this process in vivo has yet to be identified. Extracellular signal-regulated kinases (ERKs) are thought to play a pivotal role in transmitting transmembrane signals required for cell proliferation in vitro. The present studies were designed to investigate the activity, abundance, and localization of ERK1/2 in atherosclerotic lesions of cholesterol-fed rabbits. Immunofluorescence analysis revealed abundant and heterogeneous distribution of ERK1/2, mainly localized in the cap and basal regions of atheromas. A population of ERK-enriched cells was identified as ␣-actin-positive smooth muscle cells (SMCs). ERK1 and 2 were heavily phosphorylated on tyrosyl residues and coexpressed with proliferating cell nuclear antigen in atherosclerotic lesions. ERK1/2 protein levels in protein extracts from atherosclerotic lesions were 2-to 3-fold higher than the vessels of chow-fed rabbits, and their activities were elevated 3-to 5-fold over those of the normal vessel. SMCs derived from atherosclerotic lesions had increased migratory/proliferative ability and higher ERK activity in response to LDL stimulation compared with cells from the normal vessel. Inhibition of ERK activation by PD98059, a specific inhibitor of mitogen-activated protein kinase kinases (MEK1/2), abrogated LDL-induced SMC proliferation in vitro. Taken together, our findings support the proposition that persistent activation and hyperexpression of ERK1/2 may be a critical element to initiate and perpetuate cell proliferation during the development of atherosclerosis.

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“…1 The majority of cholesterol is transported into the cells by a receptor-mediated endocytosis through binding to its classic LDL receptor via apo B 100 . 2 There is evidence that LDL stimulates the phosphoinositide catabolism, 3 elevates intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ), stimulates the Na ϩ /H ϩ exchange, 4 and promotes the expression of c-fos 3 and egr-1 5 in VSMC. Several laboratories reported that LDL itself and in combination with classical growth factors exerts mitogenic effects on VSMC, 6 -11 endothelial cells, [7][8][9][10][11][12] and fibroblasts.…”

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confidence: 99%

Evidence That Lipoproteins Are Carriers of Bioactive Factors

Sachinidis

Kettenhofen

Seewald

et al. 1999

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Abstract-We recently demonstrated that the mitogenic effect of LDL (100 g/mL) as well as its early intracellular signaling pathway are mediated by a pertussis-toxin (PTX)-sensitive G i protein-coupled receptor that is independent from its classical receptor and involves activation of extracellular response kinases (ERK1/2) (also known as p44 mapk /p42 mapk ). In the present study we examined whether LDL-adherent factors may be responsible for some of the effects of LDL. The term "signaling activity" is used to characterize fractions that cause an increase in intracellular free Ca 2ϩ concentration or stimulate ERK1/2 and c-fos mRNA expression. LDL, HDL, and VLDL stimulate ERK1/2 with the following order of potency: LDLϾHDLϾVLDL. After delipidation of LDL with chloroform/methanol/water mixtures a PTX-sensitive signaling activity was found in one fraction arbitrarily called LDL-F. After further analysis of LDL-F compounds by high pressure liquid chromatography, a PTX-sensitive signaling activity was detected only in the fraction with a retention time of 33 minutes (arbitrarily called LDL-F33). Similarly, after separation of sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPC) by high pressure liquid chromatography, a PTX-sensitive signaling activity was found in the fractions 33 and 33 to 35, respectively. These findings demonstrate that the effects of LDL-F33 are mimicked by similar fractions collected from SPP/SPC, hence suggesting that these LDL-adherent molecules are possibly closely related to SPP/SPC. A PTX-sensitive signaling activity was also detected in HDL and HDL-F33. Therefore, LDL and other lipoproteins may function as carriers for bioactive phospholipids thereby contributing to the development of coronary artery disease. Our findings support a new research concept that may contribute in elucidating cellular mechanisms promoting coronary artery disease.

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Lipoproteins Induce Expression of the Early Growth Response Gene-1 in Vascular Smooth Muscle Cells from Rat

Cited by 31 publications

References 0 publications

Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB

Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB

Hyperexpression and Activation of Extracellular Signal–Regulated Kinases (ERK1/2) in Atherosclerotic Lesions of Cholesterol-Fed Rabbits

Evidence That Lipoproteins Are Carriers of Bioactive Factors

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