Induction of connective tissue growth factor (CTGF) in human endothelial cells by lysophosphatidic acid, sphingosine-1-phosphate, and platelets

Muehlich, Susanne; Schneider, Nadine; Hinkmann, Fabian; Garlichs, Christoph D.; Goppelt‐Struebe, Margarete

doi:10.1016/j.atherosclerosis.2004.04.011

Cited by 60 publications

(52 citation statements)

References 33 publications

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“…CTGF expression is increased by high glucose (47,48), as well as being elevated in fatty liver disease (49,50), and atherosclerotic plaques (51). A possible link between fatty acid metabolism and CTGF expression is indicated by the observation that sphingosine 1-phosphate, signaling through sphingosine 1-phosphate receptors, directly increases CTGF mRNA in mesangial cells (52), smooth muscle (53), fibroblasts (54), and endothelial cells (55). Another possibility is that extracellular fatty acids are signaling directly through cell surface receptors, such as the toll-like receptors or others, which are present in skeletal muscle (56,57).…”

Section: Discussionmentioning

confidence: 99%

Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration

et al. 2007

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Lipid oversupply plays a role in developing insulin resistance in skeletal muscle, decreasing expression of nuclearencoded mitochondrial genes, and increasing extracellular matrix remodeling. To determine if a decrease in plasma lipid content reverses these abnormalities, insulin-resistant subjects with a family history of type 2 diabetes had euglycemic clamps and muscle biopsies before and after acipimox treatment to suppress free fatty acids. Free fatty acids fell from 0.584 ؎ 0.041 to 0.252 ؎ 0.053 mmol/l (P < 0.001) and glucose disposal increased from 5.28 ؎ 0.46 to 6.31 ؎ 0.55 mg ⅐ kg ؊1 ⅐ min ؊1 (P < 0.05) after acipimox; intramuscular fatty acyl CoA decreased from 10.3 ؎ 1.9 to 4.54 ؎ 0.82 pmol/mg muscle (P < 0.01). Paradoxically, expression of PGC-1-and nuclear-encoded mitochondrial genes decreased after acipimox, and expression of collagens I and III ␣-subunits (82-and 21-fold increase, respectively, P < 0.05), connective tissue growth factor (2.5-fold increase, P < 0.001), and transforming growth factor-␤1 increased (2.95-fold increase, P < 0.05). Therefore, a reduction in lipid supply does not completely reverse the molecular changes associated with lipid oversupply in muscle. Changes in expression of nuclearencoded mitochondrial genes do not always correlate with changes in insulin sensitivity. Diabetes 56:743-752, 2007

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Section: Discussionmentioning

confidence: 99%

Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration

et al. 2007

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“…In light of these data, the finding that CTGF protein is overexpressed in complicated plaques and correlates positively with the numbers of inflammatory cells within the plaque may underscore the pathophysiologic importance of this growth factor in the progression of atherosclerosis. CTGF gene expression in ECs and SMCs is strongly upregulated by various cytokines (TGF-␤, platelet- derived growth factor, and basic fibroblast growth factor 16 ), it was also reported to be induced in ECs by hypoxia, 17 lipid mediators, 18 and nonuniform shear stress. 19 In the inflammatory fibroproliferative conditions of atherosclerosis, all these factors may act in concert to enhance CTGF protein production by ECs and SMCs.…”

Section: Discussionmentioning

confidence: 99%

Connective Tissue Growth Factor Is Overexpressed in Complicated Atherosclerotic Plaques and Induces Mononuclear Cell Chemotaxis In Vitro

Cicha

Yılmaz²,

Klein³

et al. 2005

ATVB

113

100

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Objective-Atherosclerotic blood vessels overexpress connective tissue growth factor (CTGF) mRNA, but the role of CTGF in atherosclerosis remains controversial. To assess the hypothesis that CTGF is involved in atherosclerotic plaque progression, we investigated CTGF protein expression and distribution in the different types of plaque morphology. Methods and Results-Serial cross-sections of 45 human carotid plaques were immunohistochemically analyzed for the presence of CTGF protein, neovascularization (von Willebrand factor), macrophages (CD68), and T cells (CD3). The lesions were categorized according to American Heart Association (AHA) classification as fibrous (type IV and V) or complicated plaques (type VI). The levels of CTGF were significantly higher in complicated compared with fibrous plaques (Pϭ0.002). CTGF accumulated particularly in the rupture-prone plaque shoulder and in the areas of neovascularization or infiltration with inflammatory cells. Macrophage-like cells stained positive for CTGF protein in plaques. Subsequent in vitro studies showed that although monocyte-derived macrophages do not produce CTGF on stimulation with transforming growth factor-␤, lipopolysaccharide, or thrombin, they take it up from culture medium. Furthermore, CTGF induces mononuclear cell chemotaxis in a dose-dependent manner. Key Words: connective tissue growth factor Ⅲ atherosclerosis Ⅲ plaque development Ⅲ chemotaxis A therosclerosis is a chronic multifactorial disease characterized by the accumulation of lipids, fibrous tissue, and inflammatory cells in the large arteries. Whereas the earliest type of lesion consists mainly of lipid-laden foam cells and some T cells, the feature of advanced lesions is the accumulation of lipid-rich necrotic debris, encapsulated by a fibrous cap consisting of extracellular matrix produced by smooth muscle cells (SMCs). In the process of plaque development, complex cellular interactions between cells of the vessel wall and the immune system result in thinning of the fibrous cap, growing lipid core, increased inflammatory activity, and neovascularization. These processes lead to plaque instability and may result in plaque rupture, which is a common pathogenetic feature in a majority of acute manifestations of atherosclerosis, such as acute coronary syndrome and stroke. 1 Connective tissue growth factor (CTGF), a potent angiogenic, chemotactic, and extracellular matrix-inducing growth factor, is produced by a wide variety of cells, including endothelial cells (ECs), SMCs, and fibroblasts. At low levels, CTGF supports wound healing by connective tissue formation after tissue injury and plays a role in angiogenesis and skeletal development. 2 However, overexpression of CTGF gene was implicated in progression of many chronic inflammatory-fibroproliferative disorders, such as glomerulosclerosis, pulmonary fibrosis, and cirrhosis. 3 As reported by Oemar et al, 4 CTGF mRNA is expressed at very high levels in atherosclerotic but not in normal human blood vessels. CTGF-producing cells in plaques...

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“…CTGF is coded for by an immediate-early response gene and, apart from VEGF (16), is rapidly induced in endothelial cells by soluble mediators such as transforming growth factorh (17) or bioactive lipids (18). Furthermore, CTGF expression in endothelial cells is regulated by mechanical stimuli.…”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Connective Tissue Growth Factor in Endothelial Cells by the Microtubule-Destabilizing Agent Combretastatin A-4

Samarin

Rehm²,

Krueger³

et al. 2009

Molecular Cancer Research

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Incubation of microvascular endothelial cells with combretastatin A-4 phosphate (CA-4P), a microtubule-destabilizing compound that preferentially targets tumor vessels, altered cell morphology and induced scattering of Golgi stacks. Concomitantly, CA-4P up-regulated connective tissue growth factor (CTGF/CCN2), a pleiotropic factor with antiangiogenic properties. In contrast to the effects of other microtubule-targeting agents such as colchicine or nocodazole, up-regulation of CTGF was only detectable in sparse cells, which were not embedded in a cell monolayer. Furthermore, CA-4P induced CTGF expression in endothelial cells, forming tube-like structures on basement membrane gels. Up-regulation of CTGF by CA-4P was dependent on Rho kinase signaling and was increased when p42/44 mitogen-activated protein kinase was inhibited. Additionally, FoxO transcription factors were identified as potent regulators of CTGF expression in endothelial cells. Activation of FoxO transcription factors by inhibition of phosphatidylinositol 3-kinase/AKT signaling resulted in a synergistic increase in CA-4P-mediated CTGF induction. CA-4P-mediated expression of CTGF was thus potentiated by the inhibition of kinase pathways, which are targets of novel antineoplastic drugs. Up-regulation of CTGF by low concentrations of CA-4P may thus occur in newly formed tumor vessels and contribute to the microvessel destabilization and antiangiogenic effects of CA-4P observed in vivo. (Mol Cancer Res 2009;7(2):180–8)

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Induction of connective tissue growth factor (CTGF) in human endothelial cells by lysophosphatidic acid, sphingosine-1-phosphate, and platelets

Cited by 60 publications

References 33 publications

Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration

Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration

Connective Tissue Growth Factor Is Overexpressed in Complicated Atherosclerotic Plaques and Induces Mononuclear Cell Chemotaxis In Vitro

Up-Regulation of Connective Tissue Growth Factor in Endothelial Cells by the Microtubule-Destabilizing Agent Combretastatin A-4

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