Demystified.
Nitric oxide.
Stuart-Smith,
K. Mol. Pathol. 55:360-366 (02)
The discovery of nitric oxide (NO) demonstrated that cells could
communicate via the manufacture and local diffusion of an unstable
lipid soluble molecule. Since the original demonstration of the
vascular relaxant properties of endothelium derived NO, this fascinating
molecule has been shown to have multiple, complex roles within
many biological systems. This review cannot hope to cover all
of the recent advances in NO biology, but seeks to place the discovery
of NO in its historical context, and show how far our understanding
has come in the past 20 years. The role of NO in mitochondrial
respiration, and consequently in oxidative stress, is described
in detail because these processes probably underline the importance
of NO in the development of disease.
Endothelial
nitric oxide synthase: the Cinderella of inflammation?
Cirino
G, Fiorucci S, Sessa WC. Trends Pharmacol Sci 24:91-95 (03)
A hallmark of inflammation is increased vascular permeability.
Increases in vascular permeability and the migration of inflammatory
cells are linked to complex interactions of inflammatory mediators
with the vascular endothelium. Normally, endothelial nitric oxide
synthase (eNOS) produces a tonic amount of nitric oxide (NO),
which is responsible for the homeostasis between the endothelium
and surrounding tissues. However, most agonists that act on endothelial
cells cause a series of post-translational modifications that
influence eNOS activity. Furthermore, stimulation by shear stress,
autacoids or growth factors either induces eNOS or shifts it to
a more active state, which produces a burst of NO. Here, we highlight
recent findings about eNOS and propose how new pharmacological
tools can be used to dissect the involvement and contribution
of eNOS to inflammatory responses.
Multiple
roles of nitric oxide in the airways.
Ricciardolo
FL. Thorax 58:175-182 (2003)
Nitric oxide is endogenously released in the airways by nitric
oxide synthase. Functionally, two isoforms of this enzyme exist:
constitutive and inducible. The former seems to protect airways
from excessive bronchoconstriction while the latter has a modulatory
role in inflammatory disorders of the airways such as asthma.
This review explores the physiological and pathophysiological
role of endogenous nitric oxide in the airways, and the clinical
aspects of monitoring nitric oxide in exhaled air of patients
with respiratory disease.
Proteolytic
degradation of nitric oxide synthase: effect of inhibitors and
role of hsp90-based chaperones.
Osawa
Y, Lowe ER, Everett AC, Dunbar AY, Billecke SS. J Pharmacol Exp
Ther 304:493-497 (2003)
Nitric oxide synthase (NOS) is a highly regulated enzyme that
produces nitric oxide, a critical messenger in many physiological
processes. In this perspective, we explore the role of proteolytic
degradation of NOS, in particular the inducible and neuronal isoforms
of NOS, as a mechanism of regulation of the enzyme. The ubiquitin-proteasome
and calpain pathways are the major proteolytic systems identified
to date that are responsible for this regulated degradation. The
degradation of NOS is affected by diverse agents, including glucocorticoids,
caveolin, neurotoxic compounds, and certain NOS inhibitors. Some
irreversible inactivators of NOS enhance the proteolytic degradation
of the enzyme, and this property may be of great importance in
understanding the biological effects of these inhibitors, some
of which are being developed for clinical use. Analogies with
the regulated degradation of liver microsomal cytochromes P450,
which are related to NOS, provide a framework for understanding
these processes. Finally, a new perspective on the regulation
of NOS by hsp90-based chaperones is presented that involves facilitated
heme insertion into the enzyme.
Plant
haemoglobins, nitric oxide and hypoxic stress.
Dordas
C, Rivoal J, Hill RD. Ann Bot 91 Spec No:173-178 (03)
It is now known that there are several classes of haemoglobins
in plants. A specialized class of haemoglobins, symbiotic haemoglobins,
were discovered 62 years ago and are found only in nodules of
plants capable of symbiotic nitrogen fixation. Plant haemoglobins,
with properties distinct from symbiotic haemoglobins were discovered
18 years ago and are now believed to exist throughout the plant
kingdom. They are expressed in different organs and tissues of
both dicot and monocot plants. They are induced by hypoxic stress
and by oversupply of certain nutrients. Most recently, truncated
haemoglobins have been shown to also exist in plants. While hypoxic
stress-induced haemoglobins are widespread in the plant kingdom,
their function has not been elucidated. This review discusses
the recent findings regarding the function of these haemoglobins
in relation to adaptation to hypoxia in plants. We propose that
nitric oxide is an important metabolite in hypoxic plant cells
and that at least one of the functions of hypoxic stress-induced
haemoglobins is to modulate nitric oxide levels in the cell.
Nitric
oxide-induced mitochondrial dysfunction: Implications for Neurodegeneration
Stewart,
VC, Heales, JR. Free Rad Biol Med 34:287-303 (03)
Excessive generation of nitric oxide (NO) has been implicated
in the pathogenesis of several neurodegenerative disorders. Damage
to the mitochondrial electron transport chain has also been implicated
in these disorders. NO and its toxic metabolite peroxynitrite
(ONOO(-)) can inhibit the mitochondrial respiratory chain, leading
to energy failure and ultimately cell death. There appears to
be a differential susceptibility of brain cell types to NO/ONOO(-),
which may be influenced by factors including cellular antioxidant
status and the ability to maintain energy requirements in the
face of marked respiratory chain damage. Although formation of
NO/ONOO(-) following cytokine exposure does not affect astrocyte
survival, these molecules may diffuse out and cause mitochondrial
damage to neighboring NO/ONOO(-)-sensitive cells such as neurons.
Evidence suggests that NO/ONOO(-) causes release of neuronal glutamate,
leading to glutamate-induced activation of neuronal NO synthase
and generation of further damaging species. While neurons appear
able to recover from short-term exposure to NO/ONOO(-), extending
the period of exposure results in persistent damage to the respiratory
chain and cell death ensues. These findings have important implications
for acute infection vs. chronic neuroinflammatory disease states.
The evidence for NO/ONOO(-)-mediated mitochondrial damage in neurodegenerative
disorders is reviewed and potential therapeutic strategies are
discussed. |
