Open AccessNicotine induces endothelial dysfunction and promotes atherosclerosis via GTPCH 1
Author(s) -
Li Jingyuan,
Liu Shangming,
Cao Guangqing,
Sun Yuanyuan,
Chen Weiqian,
Dong Fajin,
Xu Jinfeng,
Zhang Cheng,
Zhang Wencheng
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13812
Subject(s) - endothelial dysfunction , nicotine , tetrahydrobiopterin , gtp cyclohydrolase i , umbilical vein , biopterin , nitric oxide , pharmacology , in vivo , medicine , chemistry , endocrinology , nitric oxide synthase , biology , in vitro , biochemistry , microbiology and biotechnology
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 ( GTPCH 1), the rate‐limiting enzyme for de novo tetrahydrobiopterin ( BH 4) 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 GTPCH 1 and led to endothelial dysfunction. GTPCH 1 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 GTPCH 1 3′ untranslated region and increased its stability; nicotine inhibited HuR translocation from the nucleus to cytosol, which downregulated GTPCH 1. In vivo, nicotine induced endothelial dysfunction and promoted atherosclerosis in ApoE −/− mice, which were attenuated by GTPCH 1 overexpression or BH 4 supplement. Our findings may provide a novel and promising approach to atherosclerosis treatment.