Transcriptional activation of low density lipoprotein receptor gene by angiotensin-converting enzyme inhibitors and Ca(2+)-channel blockers involves protein kinase C isoforms.

Block, Lutz H.; Keul, Radovan; Crabos, Maryse; Ziesche, Rolf; Roth, Michael

doi:10.1073/pnas.90.9.4097

Cited by 17 publications

(2 citation statements)

References 37 publications

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“…In addition to cholesterol and its derivatives, LDLR transcription is also subject to regulation by physiological non-sterol mediators, including growth hormone (13,14), hepatocyte growth factor (15), cytokines (16), and some pharmaceuticals (17). The increased transcription of the LDLR gene induced by these agents has been ascribed to activation of protein kinase C, protein kinase A, and an increase in intracellular Ca 2ϩ (18,19).…”

Section: From the Department Of Veterans Affairs Palo Alto Health Carmentioning

confidence: 99%

Induction of Low Density Lipoprotein Receptor (LDLR) Transcription by Oncostatin M Is Mediated by the Extracellular Signal-regulated Kinase Signaling Pathway and the Repeat 3 Element of the LDLR Promoter

Liu

Kraemer

Ahlborn

et al. 1999

Journal of Biological Chemistry

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Oncostatin M (OM) activates the transcription of the human low density lipoprotein receptor (LDLR) inHepG2 cells through a sterol-independent mechanism. Our previous studies showed that mutations within the repeat 3 sequence of the LDLR promoter significantly decreased OM activity on LDLR promoter luciferase reporter constructs that contain the sterol responsive element-1 (repeat 2) and Sp1 binding sites (repeats 1 and 3). In this study, we investigated the signal transduction pathways that are involved in OM-induced LDLR transcription. In HepG2 cells, OM induced a rapid increase in LDLR mRNA expression, with increases detected at 30 min and maximal induction at 1 h. This OM effect was not blocked by protein synthesis inhibitors, inhibitors of p38 kinase, phosphatidylinositol 3-kinase, or c-Jun Nterminal kinase, but OM activity was completely abolished by pretreating cells with inhibitors of the extracellular signal-regulated kinase (ERK) kinase (mitogen/ ERK kinase (MEK)). To investigate whether the repeat 3 sequence of the LDLR promoter is the OM-responsive element that converts ERK activation at the promoter level, three luciferase reporters, pLDLR-TATA containing only the TATA-like elements of the promoter, pLDLR-R3 containing repeat 3 and the TATA-like elements, and pLDLR-234 containing repeats 1, 2, 3 and the TATA-like elements were constructed and transiently transfected into HepG2 cells. OM had no effect on the basal promoter construct pLDLR-TATA; however, including a single copy of repeat 3 sequence in the TATA vector (pLDLR-R3) resulted in a full OM response. The activity of OM on pLDLR-R3 was identical to that of pLDLR-234. Importantly, the ability of OM to increase luciferase activities in both pLDLR-R3-and pLDLR-234-transfected cells was blocked in a dose-dependent manner by inhibition of MEK. These results demonstrate that the mitogen-activated protein kinase MEK/ERK cascade is the essential signaling pathway by which OM activates LDLR gene transcription and provide the first evidence that the repeat 3 element is a new downstream target of ERK activation.

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Section: From the Department Of Veterans Affairs Palo Alto Health Carmentioning

confidence: 99%

Induction of Low Density Lipoprotein Receptor (LDLR) Transcription by Oncostatin M Is Mediated by the Extracellular Signal-regulated Kinase Signaling Pathway and the Repeat 3 Element of the LDLR Promoter

Liu

Kraemer

Ahlborn

et al. 1999

Journal of Biological Chemistry

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“…33 Inhibition of the calcium-related signaling pathways was shown to downregulate various genes, but upregulation of a few genes was also reported, including interleukin-6 53 and the LDL receptor. 54 Involvement of protein kinase C was suggested for the latter case. Further investigation is required to clarify exact mechanism by which verapamil and other calcium channel blockers induce ABCA1 expression and potentially increase HDL.…”

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confidence: 99%

Verapamil Increases the Apolipoprotein-Mediated Release of Cellular Cholesterol by Induction of ABCA1 Expression Via Liver X Receptor-Independent Mechanism

Suzuki

Nishimaki-Mogami

Tamehiro

et al. 2004

ATVB

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Objective-Release of cellular cholesterol and phospholipid mediated by helical apolipoprotein and ATP-binding cassette transporter (ABC) A1 is a major source of plasma HDL. We investigated the effect of calcium channel blockers on this reaction. Methods and Results-Expression of ABCA1, apoA-I-mediated cellular lipid release, and HDL production were enhanced in cAMP analogue-treated RAW264 cells by verapamil, and similar effects were also observed with other calcium channel blockers. The verapamil treatment resulted in rapid increase in ABCA1 protein and its mRNA, but not the ABCG1 mRNA, another target gene product of the nuclear receptor liver X receptor (LXR). By using the cells transfected with a mouse ABCA1 promoter-luciferase construct (Ϫ1238 to ϩ57bp), verapamil was shown to enhance the transcriptional activity. However, it did not increase transcription of LXR response element-driven luciferase vector. Conclusions-The data demonstrated that verapamil increases ABCA1 expression through LXR-independent mechanismand thereby increases apoA-I-mediated cellular lipid release and production of HDL. Key Words: calcium channel blocker Ⅲ verapamil Ⅲ ABCA1 Ⅲ HDL Ⅲ cholesterol Ⅲ apolipoprotein Ⅲ macrophage I t is a well-known fact that the risk of cardiovascular disease inversely correlates with the plasma level of high-density lipoprotein (HDL). 1,2 The background hypothesis for this finding is that HDL functions to transport cholesterol from somatic cells to the liver for its conversion to bile acids; therefore, it is believed that HDL also removes cholesterol pathologically accumulated in the cells of arterial walls as an initial stage of atherosclerosis. 3 HDL removes cellular cholesterol by two independent mechanisms: bidirectional exchange of cholesterol molecules between cell surface and HDL, in which cholesterol acyl-esterification on HDL creates its net efflux from the cells, and the interaction of helical apolipoproteins, perhaps dissociated from HDL with cellular surface to generate new HDL particles with the cellular lipid. 4 The latter reaction, initially described for macrophages 5 and then for other types of cells, 6 was found defective in the cells from the patients with genetic HDL deficiency, Tangier disease, 7,8 and in those treated with HDL-lowering drug probucol. 9,10 Therefore, the reaction is assumed as a main source of plasma HDL. Mutations in ATP-binding cassette transporter (ABC) A1, one of the ABC superfamily members, were identified in Tangier disease and other genetic HDL deficiencies to indicate that this membrane protein is a key for generation of plasma HDL. [11][12][13] Forced expression of ABCA1 led to the increase of apolipoprotein-mediated lipid release from cells, 14,15 and its overexpression in mice resulted in a mild elevation of HDL cholesterol, 16,17 implicating that expression level of this protein is a rate-limiting factor for production of plasma HDL. Accordingly, the increase of ABCA1 expression has been shown to protect the animals against atherosclerosis in certain limite...

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Vascular renin-angiotensin-system, endothelial function and atherosclerosis?

Holtz

Goetz

1994

Arteriosclerosis

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Transcriptional activation of low density lipoprotein receptor gene by angiotensin-converting enzyme inhibitors and Ca(2+)-channel blockers involves protein kinase C isoforms.

Abstract: The pharmacological potency of angiotensinconverting enzyme (ACE) inhibitors (lisinopril and enalaprilat) on the transcription of low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase genes was examined in human vascular smooth muscle ceils and compared with

Cited by 17 publications

References 37 publications

Induction of Low Density Lipoprotein Receptor (LDLR) Transcription by Oncostatin M Is Mediated by the Extracellular Signal-regulated Kinase Signaling Pathway and the Repeat 3 Element of the LDLR Promoter

Induction of Low Density Lipoprotein Receptor (LDLR) Transcription by Oncostatin M Is Mediated by the Extracellular Signal-regulated Kinase Signaling Pathway and the Repeat 3 Element of the LDLR Promoter

Verapamil Increases the Apolipoprotein-Mediated Release of Cellular Cholesterol by Induction of ABCA1 Expression Via Liver X Receptor-Independent Mechanism

Vascular renin-angiotensin-system, endothelial function and atherosclerosis?

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