Lysophosphatidic Acid Induces Early Growth Response-1 (Egr-1) Protein Expression via Protein Kinase Cδ-regulated Extracellular Signal-regulated Kinase (ERK) and c-Jun N-terminal Kinase (JNK) Activation in Vascular Smooth Muscle Cells

Iyoda, Takuya; Zhang, Fuqiang; Sun, Longsheng; Feng, Hao; Schmitz‐Peiffer, Carsten; Xu, Xuemin; Cui, Mei‐Zhen

doi:10.1074/jbc.m111.335695

Cited by 36 publications

(33 citation statements)

References 33 publications

(30 reference statements)

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“…Different subunits of G α proteins can modulate intracellular signaling cascades. An activation of protein kinase C-θ or c-Jun N-terminal kinases and thereby a negative phosphorylation of IRS could be considered as a possible mechanism involved in LPA signaling [31-33]. Furthermore the activation of GSK-3ß and S6K can also impair intracellular insulin signaling via phosphorylation of IRS [34].…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

Fayyaz

Japtok

Schumacher

et al. 2017

Cell Physiol Biochem

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Background/Aims: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA_1-6). Methods: The activation of phosphatidylinositide 3-kinases (PI₃K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Results: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI₃K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA₃-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). Conclusion: LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA₃ receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

Fayyaz

Japtok

Schumacher

et al. 2017

Cell Physiol Biochem

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“…In mouse macrophages, inhibition of in ERK1/2 phosphorylation and activation resulted in reduced Egr-1-induced tissue factor (TF) expression. Lysophosphatidic acid-induced Egr-1 expression has also been shown to be dependent on the MEK/ERK and JNK cascades (26). Importantly, increased levels of ERK phosphorylation have been demonstrated in mouse and rat lung tissues and in the medial layer of vascular lesions in several models of experimental PH (2,33,47).…”

Section: Discussionmentioning

confidence: 99%

PDGF induces SphK1 expression via Egr-1 to promote pulmonary artery smooth muscle cell proliferation

Sysol

Natarajan

Machado

2016

American Journal of Physiology-Cell Physiology

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Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease for which there is currently no curative treatment available. Pathologic changes in this disease involve remodeling of the pulmonary vasculature, including marked proliferation of pulmonary artery smooth muscle cells (PASMCs). Recently, the bioactive lipid sphingosine-1-phosphate (S1P) and its activating kinase, sphingosine kinase 1 (SphK1), have been shown to be upregulated in PAH and promote PASMC proliferation. The mechanisms regulating the transcriptional upregulation of SphK1 in PASMCs are unknown. In this study, we investigated the role of platelet-derived growth factor (PDGF), a PAH-relevant stimuli associated with enhanced PASMC proliferation, on SphK1 expression regulation. In human PASMCs (hPASMCs), PDGF significantly increased SphK1 mRNA and protein expression and induced cell proliferation. Selective inhibition of SphK1 attenuated PDGF-induced hPASMC proliferation. In silico promoter analysis for SphK1 identified several binding sites for early growth response protein 1 (Egr-1), a PDGF-associated transcription factor. Luciferase assays demonstrated that PDGF activates the SphK1 promoter in hPASMCs, and truncation of the 5'-promoter reduced PDGF-induced SphK1 expression. Stimulation of hPASMCs with PDGF induced Egr-1 protein expression, and direct binding of Egr-1 to the SphK1 promoter was confirmed by chromatin immunoprecipitation analysis. Inhibition of ERK signaling prevented induction of Egr-1 by PDGF. Silencing of Egr-1 attenuated PDGF-induced SphK1 expression and hPASMC proliferation. These studies demonstrate that SphK1 is regulated by PDGF in hPASMCs via the transcription factor Egr-1, promoting cell proliferation. This novel mechanism of SphK1 regulation may be a therapeutic target in pulmonary vascular remodeling in PAH.

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“…Egr-1 plays a crucial regulatory role in the pathogenesis of the cardiovascular system including myocardial hypertrophy, ischemia, angiogenesis, and atherosclerosis. LPA induces Egr-1 synthesis in VSMCs through the signaling pathway of LPA 1 receptor and the PKC-activated MAPKs including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) (66). …”

Section: Lpls and Vascular Metabolic Diseasementioning

confidence: 99%

Lysophospholipids and their G protein-coupled receptors in atherosclerosis

Li²,

Samuel

et al. 2016

Front Biosci

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Lysophospholipids (LPLs) are bioactive lipid-derived signaling molecules generated by the enzymatic and chemical processes of regiospecific phospholipases on substrates such as membrane phospholipids (PLs) and sphingolipids (SLs). They play a major role as extracellular mediators by activating G-protein coupled receptors (GPCRs) and stimulating diverse cellular responses from their signaling pathways. LPLs are involved in various pathologies of the vasculature system including coronary heart disease and hypertension. Many studies suggest the importance of LPLs in their association with the development of atherosclerosis, a chronic and severe vascular disease. This paper focuses on the pathophysiological effects of different lysophospholipids on atherosclerosis, which may promote the pathogenesis of myocardial infarction and strokes. Their atherogenic biological activities take place in vascular endothelial cells, vascular smooth muscle cells, fibroblasts, monocytes and macrophages, dendritic cells, T-lymphocytes, platelets, etc.

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Lysophosphatidic Acid Induces Early Growth Response-1 (Egr-1) Protein Expression via Protein Kinase Cδ-regulated Extracellular Signal-regulated Kinase (ERK) and c-Jun N-terminal Kinase (JNK) Activation in Vascular Smooth Muscle Cells

Cited by 36 publications

References 33 publications

Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

PDGF induces SphK1 expression via Egr-1 to promote pulmonary artery smooth muscle cell proliferation

Lysophospholipids and their G protein-coupled receptors in atherosclerosis

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