Biomedical Engineering Reference
In-Depth Information
Endothelial nitric oxide synthase is a plasmalemmal protein. It can be confined to
caveolae in endothelial cells, as it binds to caveolin, particularly caveolin-1 [
1107
].
Caveolin-1 inactivates NOS. Caveolae thus act as temporal and spatial regulators of
NO release in endothelial cells.
169
Regulation of the Cellular Concentration of Nitric Oxide
Cellular concentration of nitric oxide relies on cytochrome-C oxidase, the
terminal enzyme (complex-IV) of the mitochondrial respiratory (electron transport)
chain [
1108
]. Cytochrome-C oxidase catalyzes both the oxidation and reduction of
nitric oxide. In its oxidized state, cytochrome-C oxidase inactivates nitric oxide.
Conversely, nitric oxide inhibits cytochrome-C oxidase.
During hypoxia, cytochrome-C oxidase shifts from oxidized to reduced form,
thereby lowering NO inactivation and fostering hypoxic vasodilation independently
of the release of
S
nitrosothiols or of the reduction of nitrite anion (NO
2
)toNOby
hemoglobin. Other sources of nitric oxide may indeed exist [
1108
]. S-nitrosylated
hemoglobin (Hb
SNO
) releases
S
nitrosothiols during deoxygenation. Hemoglobin
may operate as a nitrite reductase that reduces NO
2
to NO as hemoglobin
deoxygenates.
Inactivation of nitric oxide may also result from interaction with superoxide ions,
hemoglobin, myoglobin, accelerated auto-oxidation favored by partition within cell
membranes, and free radicals derived from eicosanoid lipoxygenase, cyclooxyge-
nases, peroxidases, or catalase [
1108
].
However, the concentration of nitric oxide is mainly regulated by cytochrome-C
oxidase in an O
2
-dependent manner. The concentration of nitric oxide depends on
the production rate by the main source, i.e., nitric oxide synthase as well as the
redox state, turnover, and oxygen concentration at which cytochrome-C oxidase is
working. The amount of nitric oxide increases at low oxygen concentration, when
the activity of cytochrome-C oxidase decays.
The intracellular redox state that relies in particular on thioredoxin and the
glutathione-glutaredoxin system
170
influences endothelial nitric oxide synthase in
endothelial cells. Activity of glutathione reductase and cytosolic (TrxR1) and mito-
chondrial (TrxR2) thioredoxin reductase influences the intracellular ratio between
reduced and oxidized glutathione, hence NOS3 function. Inhibition of glutathione
and thioredoxin reductase reduces VEGF-induced NO production [
1109
]. In the
absence of TrxR2, production of hydrogen peroxide in endothelial cells rises
169
Muscle-specific caveolin-3 inhibits NOS3 in cardiomyocytes and NOS1 in skeletal myocytes.
170
Glutaredoxins are small redox enzymes that use anti-oxidant glutathione as a cofactor.
Glutaredoxins are reduced by the oxidation of glutathione. Oxidized glutathione is then regenerated
by glutathione reductase that is constitutively active and inducible upon oxidative stress. In its
reduced state, the thiol group is able to donate an electron to unstable molecules such as reactive
oxygen species. Glutathione then becomes reactive and reacts with another reactive glutathione to
form glutathione disulfide (oxidized state). Glutathione reductase reforms reduced glutathione.
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