Cell density-dependent modulation of perlecan synthesis by dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) in vascular endothelial cells

Hara, Takato; Sakamaki, Sayaka; Ikeda, Atsuya; Nakamura, Takehiro; Yamamoto, Chika; Kaji, Toshiyuki

doi:10.2131/jts.45.109

Cited by 6 publications

(7 citation statements)

References 17 publications

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“…The structure of Cu10 is shown in Figure 1a. Because the response of vascular endothelial cells to exogenous factors is often cell density-dependent [32][33][34][35][36], both dense and sparse cultures of the cells were used in this experiment. CSE protein expression was not altered by Cu10 in dense (Figure 1b (Figure 1d, lower panels) cultures.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Induction of Cystathionine γ-Lyase, a Reactive Sulfur-Producing Enzyme, by Copper Diethyldithiocarbamate in Cultured Vascular Endothelial Cells

Fujie

Takahashi

et al. 2020

IJMS

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As toxic substances can enter the circulating blood and cross endothelial monolayers to reach parenchymal cells in organs, vascular endothelial cells are an important target compartment for such substances. Reactive sulfur species protect cells against oxidative stress and toxic substances, including heavy metals. Reactive sulfur species are produced by enzymes, such as cystathionine γ-lyase (CSE), cystathionine β-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteinyl-tRNA synthetase. However, little is known about the regulatory mechanisms underlying the expression of these enzymes in vascular endothelial cells. Bio-organometallics is a research field that analyzes biological systems using organic-inorganic hybrid molecules (organometallic compounds and metal coordinating compounds) as molecular probes. In the present study, we analyzed intracellular signaling pathways that mediate the expression of reactive sulfur species-producing enzymes in cultured bovine aortic endothelial cells, using copper diethyldithiocarbamate (Cu10). Cu10 selectively upregulated CSE gene expression in vascular endothelial cells independent of cell density. This transcriptional induction of endothelial CSE required both the diethyldithiocarbamate scaffold and the coordinated copper ion. Additionally, the present study revealed that ERK1/2, p38 MAPK, and hypoxia-inducible factor (HIF)-1α/HIF-1β pathways mediate transcriptional induction of endothelial CSE by Cu10. The transcription factors NF-κB, Sp1, and ATF4 were suggested to act in constitutive CSE expression, although the possibility that they are involved in the CSE induction by Cu10 cannot be excluded. The present study used a copper complex as a molecular probe to reveal that the transcription of CSE is regulated by multiple pathways in vascular endothelial cells, including ERK1/2, p38 MAPK, and HIF-1α/HIF-1β. Bio-organometallics appears to be an effective strategy for analyzing the functions of intracellular signaling pathways in vascular endothelial cells.

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Section: Introductionmentioning

confidence: 99%

Transcriptional Induction of Cystathionine γ-Lyase, a Reactive Sulfur-Producing Enzyme, by Copper Diethyldithiocarbamate in Cultured Vascular Endothelial Cells

Fujie

Takahashi

et al. 2020

IJMS

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“…In contrast, IL-1α induces perlecan synthesis in other cell types, such as rabbit corneal stromal cells [ 30 ] and mouse hippocampal cells [ 31 ], although whether the length and disaccharide composition of heparan sulfate chains are altered by the cytokine is unknown. Recently, we found that 2,9-dimethyl-1,10-phenanthroline and dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) modulate endothelial perlecan synthesis [ 25 ]. These two compounds increase perlecan synthesis in cultured bovine aortic endothelial cells when the cell density is high; however, the level of perlecan mRNA is unaffected by the compounds.…”

Section: Discussionmentioning

confidence: 99%

“…In the previous study, we reported a small molecule that can modulate endothelial proteoglycan species such as diethyldithiocarbamate copper(II) and 1,10-phenanthroline, both of which induce endothelial syndecan-4 expression via the p38 MAPK and hypoxia-inducible factor (HIF)-1α pathways, respectively [ 23 , 24 ]. Additionally, we had recently reported a zinc complex dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) that upregulates perlecan in a cell density dependent manner; however, this activity was due to its organic structure [ 25 ]. Therefore, we considered that an organoantimony compound PMTAS may affect endothelial perlecan synthesis owing to its nontoxicity.…”

Section: Introductionmentioning

confidence: 99%

Sb-Phenyl-N-methyl-5,6,7,12-tetrahydrodibenz[c,f][1,5]azastibocine Induces Perlecan Core Protein Synthesis in Cultured Vascular Endothelial Cells

Hara

Konishi

Yasuike

et al. 2023

IJMS

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Vascular endothelial cells synthesize and secrete perlecan, a large heparan sulfate proteoglycan that increases the anticoagulant activity of vascular endothelium by inducing antithrombin III and intensifying fibroblast growth factor (FGF)-2 activity to promote migration and proliferation in the repair process of damaged endothelium during the progression of atherosclerosis. However, the exact regulatory mechanisms of endothelial perlecan expression remain unclear. Since organic–inorganic hybrid molecules are being developed rapidly as tools to analyze biological systems, we searched for a molecular probe to analyze these mechanisms using a library of organoantimony compounds and found that the Sb-phenyl-N-methyl-5,6,7,12-tetrahydrodibenz[c,f][1,5]azastibocine (PMTAS) molecule promotes the expression of perlecan core protein gene without exhibiting cytotoxicity in vascular endothelial cells. In the present study, we characterized proteoglycans synthesized by cultured bovine aortic endothelial cells using biochemical techniques. The results indicated that PMTAS selectively induced perlecan core protein synthesis, without affecting the formation of its heparan sulfate chain, in vascular endothelial cells. The results also implied that this process is independent of the endothelial cell density, whereas in vascular smooth muscle cells, it occurred only at high cell density. Thus, PMTAS would be a useful tool for further studies on the mechanisms underlying perlecan core protein synthesis in vascular cells, which is critical in the progression of vascular lesions, such as those during atherosclerosis.

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“…Bovine aortic endothelial cells, which have been widely used in PG research [ [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] ], at 23–30 passages were cultured in a humidified atmosphere of 5% CO 2 at 37 °C in DMEM supplemented with 10% fetal bovine serum (FBS) in 35-mm dishes until 80% confluence. The cells were then incubated for 8 h at 37 °C in fresh DMEM supplemented with 10% FBS in the presence of the siRNA/Lipofectamine RNAiMAX mixture prepared as described previously [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Syndecan-1 downregulates syndecan-4 expression by suppressing the ERK1/2 and p38 MAPK signaling pathways in cultured vascular endothelial cells

Hara

Sato

Yamamoto

et al. 2021

Biochemistry and Biophysics Reports

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Syndecan-1 and syndecan-4 are members of the syndecan family of transmembrane heparan sulfate proteoglycans. Vascular endothelial cells synthesize both species of proteoglycans and use them to regulate the blood coagulation-fibrinolytic system and their proliferation via their heparin-like activity and FGF-2 binding activity, respectively. However, little is known about the crosstalk between the expressions of the proteoglycan species. Previously, we reported that biglycan, a small leucine-rich dermatan sulfate proteoglycan, intensifies ALK5–Smad2/3 signaling by TGF-β 1 and downregulates syndecan-4 expression in vascular endothelial cells. In the present study, we investigated the crosstalk between the expressions of syndecan-1 and other proteoglycan species (syndecan-4, perlecan, glypican-1, and biglycan) in bovine aortic endothelial cells in a culture system. These data suggested that syndecan-1 downregulated syndecan-4 expression by suppressing the endogenous FGF-2-dependent ERK1/2 pathway and FGF-2-independent p38 MAPK pathway in the cells. Moreover, this crosstalk was a one-way communication from syndecan-1 to syndecan-4, suggesting that syndecan-4 compensated for the reduced activity in the regulation of vascular endothelial cell functions caused by the decreased expression of syndecan-1 under certain conditions.

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Cell density-dependent modulation of perlecan synthesis by dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) in vascular endothelial cells

Cited by 6 publications

References 17 publications

Transcriptional Induction of Cystathionine γ-Lyase, a Reactive Sulfur-Producing Enzyme, by Copper Diethyldithiocarbamate in Cultured Vascular Endothelial Cells

Transcriptional Induction of Cystathionine γ-Lyase, a Reactive Sulfur-Producing Enzyme, by Copper Diethyldithiocarbamate in Cultured Vascular Endothelial Cells

Sb-Phenyl-N-methyl-5,6,7,12-tetrahydrodibenz[c,f][1,5]azastibocine Induces Perlecan Core Protein Synthesis in Cultured Vascular Endothelial Cells

Syndecan-1 downregulates syndecan-4 expression by suppressing the ERK1/2 and p38 MAPK signaling pathways in cultured vascular endothelial cells

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