Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 63

deacetylation (Mattagajasingh et al. 2007 ). SIRT1 and eNOS colocalize and
coprecipitate in endothelial cells, and SIRT1 deacetylates eNOS, stimulating eNOS
activity and increasing endothelial NO. Inhibition of SIRT1 in the endothelium of
arteries inhibits endothelium-dependent vasodilation and decreases bioavailable
NO. Finally, CR of mice leads to deacetylation of eNOS. These results demonstrate
that SIRT1 plays a fundamental role in regulating endothelial NO and endothelium-
dependent vascular tone by deacetylating eNOS. Furthermore, this study provides
a possible molecular mechanism connecting the effects of CR on the endothelium
and vascular tone to SIRT1-mediated deacetylation of eNOS.
The molecular mechanisms of eNOS regulation of microvascular permeability
remain unresolved. Agonist-induced internalization may have a role in this process.
A study has demonstrated that internalization of eNOS is required to deliver NO to
subcellular locations to increase endothelial monolayer permeability to macromole-
cules and suggests that a mechanism by which eNOS is activated by phosphorylation
at the plasma membrane and its endocytosis is required to deliver NO to subcellular
targets to cause hyperpermeability (Sánchez et al. 2009 ).
Role of NO in the Plasma Compartment
The reaction products of NO with blood conserve its bioactivity and transduce an
endocrine vasomotor function under certain conditions. Although S-nitrosated
albumin has been considered the major species subserving this activity, additional
NO species may also contribute. Human plasma consumes NO at a rate equivalent
to that of hemoglobin (Hb). This NO consumption is mediated by the reaction of
NO with plasma haptoglobin-hemoglobin complexes and limited slower reaction
pathways required for S-nitrosation. Thus, high-affinity metal-based reactions in
plasma with the haptoglobin-hemoglobin complex modulate plasmatic NO reaction
products and limit S-nitrosation at low NO flux. Therefore, alternative NO reaction
end products in plasma, such as nitrite, N-nitrosamines, iron-nitrosyls, and nitrated
lipids, should be evaluated in blood NO transport along the vasculature.
It is proposed that the bond between NO and the Hb thiol Cys-b93 (SNOHb) is
favored when Hb is in the relaxed (R, oxygenated) conformation, and that deoxygen-
ation to tense (T) state destabilizes the SNOHb bond, allowing transfer of NO from
Hb to form other (vasoactive) S-nitrosothiols (SNOs). SNO RBC is increased » 20-fold
in human septic shock and the O 2 -dependent vasoactivity of RBCs is affected pro-
foundly by SNO content in a murine lung bioassay indicating that SNO content and
O 2 saturation are tightly coupled in intact RBCs (Doctor et al. 2005 ). This coupling
is likely to be of pathophysiological significance.
Measurement of NO as a Biomarker of Cardiovascular Function
The measurement of NO bioavailability is of great clinical interest in the assess-
ment of cardiovascular health. However, NO is rapidly oxidized to form nitrite and
nitrate and thus its direct detection in biological systems is difficult. Venous
plasma nitrite (nM concentrations) has been shown to be a marker of forearm NO