Nicotine induces endothelial dysfunction and promotes atherosclerosis via GTPCH1.

Abstract

Smoking is a major preventable risk factor for atherosclerosis. However, the causative link between cigarette smoke and atherosclerosis remains to be established. The objective of this study is to characterize the role of GTP cyclohydrolase 1 (GTPCH1), the rate-limiting enzyme for de novo tetrahydrobiopterin (BH4) synthesis, in the smoking-accelerated atherosclerosis and the mechanism involved. In vitro, human umbilical vein endothelial cells were treated with nicotine, a major component of cigarette smoke, which reduced the mRNA and protein levels of GTPCH1 and led to endothelial dysfunction. GTPCH1 overexpression or sepiapterin could attenuate nicotine-reduced nitric oxide and -increased reactive oxygen species levels. Mechanistically, human antigen R (HuR) bound with the adenylateuridylate-rich elements of the GTPCH1 3' untranslated region and increased its stability; nicotine inhibited HuR translocation from the nucleus to cytosol, which downregulated GTPCH1. In vivo, nicotine induced endothelial dysfunction and promoted atherosclerosis in ApoE-/- mice, which were attenuated by GTPCH1 overexpression or BH4 supplement. Our findings may provide a novel and promising approach to atherosclerosis treatment.

• Authors: Jingyuan Li, Shangming Liu, Guangqing Cao, Yuanyuan Sun, Weiqian Chen, Fajin Dong, Jinfeng Xu, Cheng Zhang, Wencheng Zhang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 22 Issue 11 Pg. 5406-5417 (11 2018) ISSN: 1582-4934 [Electronic] England
• PMID: 30091833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Apolipoproteins E
• ELAV-Like Protein 1
• Pterins
• RNA, Messenger
• Reactive Oxygen Species
• Biopterin
• Nitric Oxide
• Nicotine
• sepiapterin
• GCH1 protein, human
• GTP Cyclohydrolase
• sapropterin

Topics

• Animals
• Apolipoproteins E (genetics)
• Atherosclerosis (chemically induced, genetics, pathology)
• Biopterin (analogs & derivatives, biosynthesis)
• ELAV-Like Protein 1 (genetics)
• Endothelial Cells (drug effects, pathology)
• GTP Cyclohydrolase (genetics)
• Gene Expression Regulation (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• Mice
• Nicotine (administration & dosage, toxicity)
• Nitric Oxide (genetics)
• Pterins (pharmacology)
• RNA, Messenger (drug effects)
• Reactive Oxygen Species (metabolism)
• Risk Factors
• Smoking (adverse effects)