Tetrahydrobiopterin and nitric oxide synthase regulation

ISBN-13: 9783639164008 / Angielski / Miękka / 2009 / 140 str.

Nicholas Alp

Opis

Nitric oxide (NO) produced by endothelial nitricoxide synthase (eNOS) is a key mediator of vascularhomeostasis. eNOS enzymatic activity appears to bedetermined by the availability of its cofactortetrahydrobiopterin (BH4). BH4 bioavailability islimited by oxidative degradation in dysfunctionalendothelium, and by alterations in the rate of itsbiosynthesis, governed by the rate-limiting enzymeGTP cyclohydrolase 1 (GTPCH). In this project noveltargeted transgenic mouse lines were generated withendothelial-specific over-expression of human GTPCH.These studies have shown that BH4 bioavailabilitywithin the endothelium is essential for maintainingNO synthesis and reducing superoxide production byeNOS in vivo. Modest persistent increases inendothelial cell BH4 concentration by increasedbiosynthesis are sufficient to maintain NObioavailability and endothelial function, even in thesetting of vascular oxidative stress. These findingssuggest that strategies to augment endothelial BH4levels, either by increased biosynthesis or byreducing BH4 oxidation, may be valuable in preventingand treating vascular disease.

O autorze

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.