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

• Published in: International journal of molecular sciences Vol. 21; no. 17; p. 6053
• Main Authors: Fujie, Tomoya, Takahashi, Akane, Takahashi, Musubu, Hara, Takato, Soyama, Asuka, Makino, Kosho, Takahashi, Hideyo, Yamamoto, Chika, Kumagai, Yoshito, Naka, Hiroshi, Kaji, Toshiyuki
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.09.2020; MDPI
• Subjects: 3-Mercaptopyruvate sulfurtransferase; Animals; Aorta; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; bio-organometallics; Blood circulation; Cadmium; Cattle; Cell density; Cells, Cultured; Copper - chemistry; Copper compounds; copper diethyldithiocarbamate; Cystathionine gamma-Lyase - genetics; Cystathionine gamma-Lyase - metabolism; cystathionine γ-lyase; Cysteine-tRNA ligase; Cytotoxicity; Ditiocarb - chemistry; Ditiocarb - pharmacology; endothelial cell; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium, Vascular - cytology; Enzymes; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Growth factors; Hazardous materials; Heavy metals; Heparan sulfate; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; hypoxia-inducible factor-1; Intracellular; Intracellular signalling; Kinases; Ligands; MAP kinase; MAP Kinase Signaling System - drug effects; mitogen-activated protein kinase; NF-κB protein; Organometallic compounds; Organs; Oxidative stress; Prostate; Protein expression; Proteins; Signal transduction; Sp1 protein; Sulfur; Sulfur - metabolism; Sulfurtransferase; Transcription factors; tRNA; Zinc; cystathionine γ-lyase; mitogen-activated protein kinase; bio-organometallics; endothelial cell; hypoxia-inducible factor-1; copper diethyldithiocarbamate
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21176053

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.