Tetrahydrobiopterin: regulator of endothelial function

Project: Research project

Project Details

Description

Endothelial dysfunction defined as a loss of biologically active nitric oxide (NO) produced in the endothelium,
is one of the most important events in initiation and progression of vascular disease. Tetrahydrobiopterin
(BH4) is an essential cofactor needed for enzymatic activity of nitric oxide synthase(s) and biosynthesis of
NO. In vivo mechanisms responsible for the control of BH4 metabolism are poorly understood. During
preliminary studies for this application we identified erythropoietin (EPO) as a novel and potent stimulator of
BH4 biosynthesis in the cardiovascular system. EPO is circulating hormone responsible for control of
erythropoiesis, however, more recent findings suggest that EPO has important non-erythropoietic effects
including vascular protection. The general hypothesis of this proposal is that in vivo, BH4 critically
contributes to the vascular protective effect of EPO. To test this hypothesis we propose studies with following
specific aims: 1) determine the role of BH4 in mediation of protective effectsof EPO in vascular endothelium,
2) determine if EPO may prevent development of atherosclerosis, and 3) analyze the mechanisms of EPO-
induced endothelial repair after vascular injury. In vivo genetic and pharmacological approaches will be used
to manipulate levels of circulating EPO and BH4. Established murine models of endothelial dysfunction and
vascular injury will be employed to determine role of BH4 in mediation of vascular protective effects of EPO.
To dissect direct effects of EPO from its rheological effects due to increase in shear stress imposed on
endothelium by circulating erythrocytes, effects of novel non-erythropoietic derivatives of EPO will be
studied. It is anticipated that the results of the proposed experiments will provide novel and important
information concerning the role of EPO in control of BH4 metabolism in the cardiovascular system. This
information may help to develop new strategies in prevention and treatment of endothelial dysfunction. .
StatusNot started

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