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Nitric Oxide. 2018 Jun 1;76:113-121. doi: 10.1016/j.niox.2018.02.009. Epub 2018 Mar 7.

Cigarette smoke constituents cause endothelial nitric oxide synthase dysfunction and uncoupling due to depletion of tetrahydrobiopterin with degradation of GTP cyclohydrolase.

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Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
College of Pharmacy, Helwan University, Cairo, Egypt.
Ohio Smoking Research Center, Columbus, OH, USA. Electronic address:
British American Tobacco, Southampton, UK.
Ohio Smoking Research Center, Columbus, OH, USA.


Cigarette smoking (CS) is a well-established risk factor for cardiovascular disease (CVD). Endothelial dysfunction (ED) with loss of nitric oxide (NO) production is a central mechanism leading to the advent of CVD. Despite many prior studies of this major health problem, the exact mechanism by which CS induces ED is not well understood. This study examines the mechanism by which CS induces ED with altered endothelial NO synthase (eNOS) function in aortic endothelial cells (AECs). Exposure of AECs to cigarette smoke extract (CSE) resulted in a marked decrease in NO production with concomitant increase in superoxide (O2.-) generation and accumulation of 4-hydroxy-2-nonenal protein adducts. CSE exposure led to depletion of the essential eNOS cofactor tetrahydrobiopterin (BH4) as well as total biopterin levels and decreased the expression level of guanosine triphosphate cyclohydrolase (GTPCH), the rate limiting enzyme in BH4 biosynthesis. Moreover, exposure of AECs to CSE increased the level of ubiquitinated proteins and increased 26 S proteasomal activity in a concentration-dependent manner. Pre-treatment with MG132, a 26 S proteasome inhibitor, partially prevented CSE-induced loss of BH4, total biopterin, GTPCH, and increased NO production following CSE exposure, indicating a role of the ubiquitin-proteasome system in CSE-induced eNOS dysfunction. In conclusion, CSE-induced eNOS dysfunction and uncoupling occurs due to BH4 depletion with BH4de novo synthesis limited by diminished GTPCH expression.


Cigarette smoking; Guanosine triphosphate cyclohydrolase; Nitric oxide synthase; Oxygen free radicals; Tetrahydrobiopterin; Ubiquitination

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