Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 22, Issue 11, Pages 5406-5417Publisher
WILEY
DOI: 10.1111/jcmm.13812
Keywords
atherosclerosis; GTPCH1; HuR; nicotine
Categories
Funding
- Sanming Project of Medicine in Shenzhen [SZSM201512025]
- National Natural Science Foundation of China [81570393, 81770473, 81600344, 81770442, 81771841, 81770258]
- Science and Technology Project of Suzhou [SYS201705]
- Shandong Provincial Natural Science Foundation, China [ZR2016HQ29]
- Taishan Scholar Project of Shandong Province of China [tsqn20161066]
- Key Research and Development Program of Shandong Province [2013GSF12114]
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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.
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