Vascular Endothelial Growth Factor Induces Expression of Connective Tissue Growth Factor via KDR, Flt1, and Phosphatidylinositol 3-Kinase-Akt-dependent Pathways in Retinal Vascular Cells

Suzuma, Kiyoshi; Naruse, Keiko; Suzuma, Izumi; Takahara, Noriko; Ueki, Kohjiro; Aiello, Lloyd Paul; King, George L.

doi:10.1074/jbc.m006509200

Cited by 230 publications

(180 citation statements)

References 60 publications

(33 reference statements)

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“…For instance, VEGF is a known target for HIF-1 and has been shown to enhance CTGF mRNA expression (62). However, the kinetics of VEGF expression in response to hypoxia would preclude it from playing a role in our observed hypoxic induction of Ctgf.…”

Section: Discussionmentioning

confidence: 41%

Hypoxic induction ofCtgfis directly mediated by Hif-1

Higgins

Biju²,

Akai³

et al. 2004

American Journal of Physiology-Renal Physiology

257

196

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CTGF plays a significant role in the development of renal fibrosis by mediating the fibrotic effects of transforming growth factor (TGF)-β1and has been shown to be hypoxia inducible in human breast cancer cells. It has been suggested that hypoxia is an important underlying cause for the development of renal fibrosis through the modulation of profibrotic genes. One of the key mediators of the cell's response to lowered oxygen environments is hypoxia-inducible-factor-1 (HIF-1), a basic helix-loop-helix transcription factor, which enables cells to adapt to hypoxia by regulating the expression of genes involved in increasing oxygen availability ( VEGF, erythropoietin) and enhancing glucose uptake and metabolism ( Glut-1, PGK). In this paper, we have used primary tubular epithelial cell cultures from a tetracycline-inducible- Hif- 1α knockout murine model to further elucidate the role of Hif-1 in the hypoxic-induction of Ctgf expression. We show that hypoxia response elements present upstream of Ctgf enable direct interaction of Hif-1 transcription factor with the Ctgf promoter, resulting in increased transcription of Ctgf mRNA. Cells deficient in Hif- 1α were incapable of inducing Ctgf mRNA in response to hypoxia, suggesting an absolute requirement of Hif-1. Furthermore, the observed Hif-1-mediated hypoxic stimulation of Ctgf expression was found to occur independently of TGF-β1signaling. Our findings have important implications for a number of fibrotic disorders in which hypoxia, CTGF, and TGF-β1are involved, including renal, dermal, hepatic, and pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 41%

Hypoxic induction ofCtgfis directly mediated by Hif-1

Higgins

Biju²,

Akai³

et al. 2004

American Journal of Physiology-Renal Physiology

257

196

View full text Add to dashboard Cite

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“…Recombinant Adenoviruses-cDNA of constitutively active Akt (CAAkt, Gag protein fused to the N terminus of wild type Akt) and cDNA of dominant-negative Akt (DN-Akt, containing Thr 308 3 Ala and Ser 473 3 Ala substitutions) have been described previously (31). cDNAs of wild type and DN JNK (K55R) have also been described previously (32).…”

Section: Methodsmentioning

confidence: 99%

Angiopoietin-1 Attenuates H2O2-induced SEK1/JNK Phosphorylation through the Phosphatidylinositol 3-Kinase/Akt Pathway in Vascular Endothelial Cells

Murakami

Takagi

Suzuma

et al. 2005

Journal of Biological Chemistry

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“…However, several lines of evidence argue against this hypothesis. First, previous studies have demonstrated that the inactive phosphorylation mutant of Akt functions effectively as a dominant-negative (22,54,55). Moreover, overexpression of the DN-Akt adenovirus inhibited insulin-induced glycogen synthase kinase-3 in L6 myoblast cells.…”

Section: Thrombin Fails To Induce Nf-b and Gata Binding To The Vcam-1mentioning

confidence: 99%

Thrombin Stimulation of Vascular Adhesion Molecule-1 in Endothelial Cells Is Mediated by Protein Kinase C (PKC)-δ-NF-κB and PKC-ζ-GATA Signaling Pathways

Minami

Abid

Zhang

et al. 2003

Journal of Biological Chemistry

105

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We recently demonstrated that thrombin induces the expression of vascular adhesion molecule-1 (VCAM-1) in endothelial cells by an NF-B-and GATA-dependent mechanism. In the present study, we describe the signaling pathways that mediate this response. Thrombin stimulation of the VCAM-1 gene and promoter in human umbilical vein endothelial cells was inhibited by preincubation with the phosphatidylinositol 3-kinase inhibitor, LY294002, the protein kinase C (PKC)-␦ inhibitor, rottlerin, a PKC-peptide inhibitor, or by overexpression of dominant negative (DN)-PKC-. In electrophoretic mobility shift assays, thrombin-mediated induction of NF-B p65 binding to two NF-B motifs in the upstream promoter region of VCAM-1 was blocked by LY294002 and rottlerin, whereas the inducible binding of GATA-2 to a tandem GATA motif was inhibited by LY294002 and the PKC-peptide inhibitor. In co-transfection assays, thrombin stimulation of a minimal promoter containing multimerized VCAM-1 NF-B sites was inhibited by DN-PKC-␦ but not DN-PKC-. In contrast, thrombin-mediated transactivation of a minimal promoter containing tandem VCAM-1 GATA motifs was inhibited by DN-PKC-but not DN-PKC-␦. Finally, thrombin failed to induce VCAM-1 expression in vascular smooth muscle cells. Taken together, these data suggest that the endothelial cell-specific effect of thrombin on VCAM-1 expression involves the coordinate activity of PKC-␦-NF-B and PKC--GATA signaling pathways. Vascular adhesion molecule-1 (VCAM-1)1 is a 110-kDa cell surface glycoprotein that is expressed in cytokine-activated endothelial cells (1). The VCAM-1 promoter, originally cloned and characterized in cultured endothelial cells (2), represents a potentially valuable tool for dissecting the molecular mechanisms of endothelial cell activation. Several studies have demonstrated the importance of two tandem NF-B elements located at position Ϫ77 and Ϫ63, relative to the transcriptional start site, in transducing the response to inflammatory mediators (2-4). Other studies have provided evidence for the role of co-stimulators in mediating cytokine response, including Sp1 (5), activating protein-1 (6), and interferon regulatory factor-1 (7).In a recent report, we showed that the incubation of endothelial cells with thrombin or the PAR-1 agonist, thrombin receptor activation peptide (TRAP), resulted in increased VCAM-1 mRNA levels and VCAM-1 promoter activity (8). Not surprisingly, a mutation of the tandem NF-B motif blocked the response to thrombin. Moreover, in electrophoretic mobility shift assays, thrombin induced the binding of p65 homodimers to the two adjacent NF-B sites in the VCAM-1 promoter. A more interesting finding was that a mutation of a tandem GATA motif (located at Ϫ244 and Ϫ259) also attenuated the thrombin response. Consistent with these results, thrombin treatment resulted in increased binding of GATA-2 to the VCAM-1 promoter. These data suggested that thrombin-mediated induction of VCAM-1 involves the coordinate activity of NF-B p65 and GATA-2 and raised new questions as to...

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Vascular Endothelial Growth Factor Induces Expression of Connective Tissue Growth Factor via KDR, Flt1, and Phosphatidylinositol 3-Kinase-Akt-dependent Pathways in Retinal Vascular Cells

Cited by 230 publications

References 60 publications

Hypoxic induction ofCtgfis directly mediated by Hif-1

Hypoxic induction ofCtgfis directly mediated by Hif-1

Angiopoietin-1 Attenuates H2O2-induced SEK1/JNK Phosphorylation through the Phosphatidylinositol 3-Kinase/Akt Pathway in Vascular Endothelial Cells

Thrombin Stimulation of Vascular Adhesion Molecule-1 in Endothelial Cells Is Mediated by Protein Kinase C (PKC)-δ-NF-κB and PKC-ζ-GATA Signaling Pathways

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