TETRAHYDROBIOPTERIN--REGULATOR OF ENDOTHELIAL FUNCTION

Project: Research project

Project Details

Description

L-Arginine/nitric oxide pathway plays a key role in regulation of arterial
tone. Biosynthesis of nitric oxide requires activation of nitric oxide
synthase in the presence of tetrahydrobiopterin as a cofactor. The
proposition to be tested is that in vascular endothelial cells suboptimal
concentrations of tetrahydrobiopterin may favor nitric oxide synthase-
catalyzed production of hydrogen peroxide. Protocols are designed to
determine if in coronary arteries with impaired tetrahydrobiopterin
biosynthesis, hydrogen peroxide may replace nitric oxide as mediator of
endothelium-dependent relaxations. Mechanisms of relaxations to hydrogen
peroxide will be studied and levels of cyclic GMP will be measured in
order to characterize the role of soluble guanylate cyclase. Hydrogen
peroxide is a potent oxidant and it is expected that these studies may
provide new information concerning the role of dysfunctional nitric oxide
synthase in endothelial injury. Since de novo synthesis of
tetrahydrobiopterin is regulated by enzymatic activity of GTP
cyclohydrolase I, molecular mechanisms regulating expression of mRNA
isoforms encoding for this protein will be studied. Activity of GTP
cyclohydrolase I and concentrations of tetrahydrobiopterin in endothelial
cells will be measured. Preliminary studies demonstrated that type 1 GTP
cyclohydrolase I is expressed in human aortic endothelial cells.
Identification of signal transduction pathways involved in control of gene
expression, as well as activity of GTP cyclohydrolase I, will provide a
molecular basis for understanding of mechanisms responsible for impairment
of tetrahydrobiopterin biosynthesis and dysfunction of nitric oxide
synthase. In order to determine whether dysfunction could be corrected by
exogenous pterins, vascular effects of tetrahydrobiopterin and 6-methyl-
tetrahydropterin on mechanisms of endothelium-dependent relaxations in
control arteries and arteries with impaired tetrahydrobiopterin
biosynthesis will be investigated. Canine basilar arteries will be used as
a model to study the inhibitory effects of pterins on endothelium-
dependent contractions. The effect of pterins on production of cyclic GMP,
cyclic AMP as well as on prostanoid production associated with
endothelium-dependent contractions will be measured. These experiments
will reveal whether pterins may affect balance between relaxing and
contracting factors released from endothelium. It is anticipated that
results of this proposal will define the role of tetrahydrobiopterin in
regulation of endothelial function. The proposed studies may also help to
identity if impaired tetrahydrobiopterin biosynthesis may contribute to
initial endothelial injury known to be a key event in the pathogenesis of
vascular diseases.
StatusFinished
Effective start/end date12/1/943/31/11

ASJC

  • Medicine(all)