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Restitution of Endothelial Function and Nitric Oxide Bioavailability in Aging Vasculature

by Dobrucki, Iwona T.

Abstract (Summary)
Advanced age is associated with endothelial dysfunction and increased risk for cardiovascular diseases. However, the molecular mechanisms of the L-arginine/endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway for this dysfunction are not clear. We determined whether a deficient NO bioactivity in aged rats results from eNOS uncoupling, producing superoxide (O 2 - ) and subsequently peroxynitrite (ONOO - ) rather than NO, and whether this effect may be antagonized by L-arginine. The kinetics of NO/O 2 - /ONOO - release were recorded ex vivo in single endothelial cells from aortas of old and young rats by tandem electrochemical NO/O 2 - /ONOO - -nanosensors before and after long-term and short-term supplementations with D-/L-arginine stereoisomers. We also tested the integrity of the L-arginine/eNOS/NO pathway by analyzing eNOS expression and activity together with changes in the concentrations of L-arginine, N G ,N G ’ -dimethylarginine (ADMA), and L-glutamine in endothelium. The aged endothelium elicited a greater potency of NO production through increased eNOS protein levels and enzyme activities compared with young endothelium. Paradoxically, due to decreased L-arginine (˜5.5-fold) and increased ADMA (˜3-fold) intracellular levels (without changes in L-glutamine concentrations), the aged endothelium exhibited reduced release of bioactive NO with concomitant increases in the eNOS-dependent release of both O 2 - and ONOO-. These age-dependent effects were reversed by supplementation with L-arginine, but not D-arginine, and were associated with restored L-arginine/ADMA concentration ratios in endothelium. Reduction of NO bioavailabilty in aged vascular endothelium is caused by an excess of O 2 - , produced by upregulated uncoupled eNOS under conditions of diminished intracellular L-arginine concentrations. The age-related uncoupling of eNOS may be reversed by L-arginine supplementation and statins treatment.
Bibliographical Information:

Advisor:

School:Ohio University

School Location:USA - Ohio

Source Type:Master's Thesis

Keywords:nitric oxide superoxide peroxynitrite aging endothelium enos uncoupling

ISBN:

Date of Publication:01/01/2004

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