Tetrahydrobiopterin and nitric oxide synthase regulation
Generation and analysis of endothelial-targeted transgenic mouse lines over-expressing human GTP cyclohydrolase 1
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Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is a key mediator of vascular homeostasis. eNOS enzymatic activity appears to be determined by the availability of its cofactor tetrahydrobiopterin (BH4). BH4 bioavailability is limited by oxidative degradation in dysfunctional endothelium, and by alterations in the rate of its biosynthesis, governed by the rate-limiting enzyme GTP cyclohydrolase 1 (GTPCH). In this project novel targeted transgenic mouse lines were generated with endothelial-specific over-expression of human GTPCH. These studies have shown that BH4 bioavailability within the endothelium is essential for maintaining NO synthesis and reducing superoxide production by eNOS in vivo. Modest persistent increases in endothelial cell BH4 concentration by increased biosynthesis are sufficient to maintain NO bioavailability and endothelial function, even in the setting of vascular oxidative stress. These findings suggest that strategies to augment endothelial BH4 levels, either by increased biosynthesis or by reducing BH4 oxidation, may be valuable in preventing and treating vascular disease.
Dr Nicholas Alp, MD PhD, is a Vascular Biologist and Consultant
Interventional Cardiologist, working at the John Radcliffe
Hospital, Oxford and at Milton Keynes Hospital NHS Foundation
Trust. He was awarded his PhD from the University of Cambridge,
and
his MD from the University of Oxford.
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Nicholas Alp: Tetrahydrobiopterin and nitric oxide synthase regulation bei hugendubel.de. Online bestellen oder in der Filiale abholen.