Contents
Nitric Oxide (NO)
Executive Editor: Ruben Zamora
The Chemical Dynamics of NO and Reactive
Nitrogen Oxides: A Practical Guide Pp.723-740
Daniele Mancardi, Lisa
A. Ridnour, Douglas D. Thomas, Tatsuo Katori, Carlo G. Tocchetti, Michael G.
Espey, Katrina M. Miranda, Nazareno Paolocci and David A. Wink
HIF-1a
and p53 as Targets of NO in Affecting Cell Proliferation, Death and Adaptation Pp.741-751
Jie Zhou, Tobias
Schmid and Bernhard Brune
Inflammatory Modulation of Hepatocyte
Apoptosis by Nitric Oxide: In Vivo, In Vitro, and In Silico
Studies Pp.753-762
Yoram Vodovotz, Peter
K. M. Kim, Elife Zerrin Bagci, G. Bard Ermentrout,Carson C. Chow, Ivet Bahar
and Timothy R. Billiar
The Role of iNOS in Chronic Inflammatory
Processes In Vivo: Is it Damage-Promoting, Protective, or Active at all?
Pp.763-775
Christoph V. Suschek,
Oliver Schnorr and Victoria Kolb-Bachofen
The Dichotomous Role of Nitric Oxide in the
Pathogenesis of Accelerated Atherosclerosis Associated with Systemic Lupus
Erythematosus Pp.777-786
Marc C. Levesque and
J. Brice Weinberg
Cross-Talk Between Nitric Oxide and
Transforming Growth Factor-β1 in Malaria Pp.787-797
Yoram Vodovotz, Ruben
Zamora, Matthew J. Lieber and Shirley Luckhart
Abstracts
[Back to top] The
Chemical Dynamics of NO and Reactive Nitrogen Oxides: A Practical Guide
Daniele Mancardi, Lisa
A. Ridnour, Douglas D. Thomas, Tatsuo Katori, Carlo G. Tocchetti, Michael G.
Espey, Katrina M. Miranda, Nazareno Paolocci and David A. Wink
Nitric oxide has emerged as one of the most
important and diverse players in physiology. This small diatomic radical
stunned researchers because of its existence and unique biological properties
in human physiology. Over the last two decades it was found that NO often has
fickle behavior in pathophysiological mechanisms. Where benefiting the host in
one case yet inducing and augmenting injury in another. This has lead to
confusion in is NO good or bad? Much of the answers to this dichotomy lies in
the chemistry of NO and its related nitrogen oxide species. To help understand
the complex chemistry with perspective to biology, a discussion on the chemical
biology of NO is useful. The chemical biology defines the relevant chemical
reaction of NO and nitrogen monoxide in the context of the biological
conditions. We discuss in this article the chemistry of nitrogen oxide with
different types of biological motifs. Reaction of NO with metal complexes and
radicals require low concentration, where formation of reactive nitrogen oxide
species require considerably higher amounts and generally are isolated to
specific microenvironments in vivo. Though many reactive nitrogen oxide
species are formed from chemical reactions with NO, there are several which
appear to not require NO to be present, HNO and NO2. These two
species have unique physiological effects and represent additional complexity
to this biological picture. From this discussion, a picture can be formed
concerning the possible chemical dynamics, which can be plausible in different
biological mechanisms.
[Back to top] HIF-1a and p53 as Targets of NO in Affecting Cell
Proliferation, Death and Adaptation
Jie Zhou, Tobias
Schmid and Bernhard Brune
During the past years nitric oxide (NO) signaling
became an integral component in understanding physiological and
pathophysiological processes of cell proliferation, death or cellular
adaptation. Among other activities NO affects multiple targets that allow
regulation of gene expression. Although there is no evidence for direct
NO-responsive DNA elements within promotor regions of eukaryotic genes numerous
indirect signaling pathways exist to explain NO-regulated gene expression. A
characteristic feature of some transcription factors such as hypoxia inducible
factor-1a (HIF-1a) or
p53 (tumor suppressor p53) is their low protein abundance in unstressed cells
due to efficient 26S proteasomal degradation of the protein.
Characteristically, the protein amount of HIF-1a or
p53 is increased steeply upon hypoxic stress or mechanisms that require
activation of “guardian of the genome”, i.e. p53. Current available data
illustrate that NO is endowed with the ability to mimic a hypoxic response by
stabilizing HIF-1α and/or to accumulate p53 and thus to affect viability
decisions. Here we review recent advances in understanding molecular mechanisms
how NO affects stability regulation of HIF-1a and
p53. Moreover, we summarize existing concepts how HIF-1a and p53 interact to direct proliferation,
death or adaptation. Considering HIF-1a and
p53 as targets of reactive nitrogen intermediates (RNI) may provide insights
into basic chemical reactions, biochemical signal transduction pathways with
broad implications for medicine.
[Back to top]
Inflammatory
Modulation of Hepatocyte Apoptosis by Nitric Oxide: In Vivo, In Vitro,
and In Silico Studies
Yoram Vodovotz, Peter
K. M. Kim, Elife Zerrin Bagci, G. Bard Ermentrout,Carson C. Chow, Ivet Bahar
and Timothy R. Billiar
Nitric oxide (NO•) and its reaction products
are key players in the physiology and pathophysiology of inflammatory settings
such as sepsis and shock. The consequences of the expression of inducible NO•
synthase (iNOS, NOS-2) can be either protective or damaging to the liver. We
have delineated two distinct hepatoprotective actions of NO•: the stimulation
of cyclic guanosine monophosphate and the inhibition of caspases by
S-nitrosation. In contrast, iNOS/NO• promotes hepatocyte death under conditions
of severe redox stress, such as hemorrhagic shock or ischemia/reperfusion.
Redox stress activates an unknown molecular switch that transforms NO•, which
is hepatoprotective under resting conditions, into an agent that induces
hepatocyte death. We hypothesize that the magnitude of the redox stress is a
major determinant for the effects of NO• on cell survival by controlling the
chemical fate of NO•. To address this hypothesis, we have carried out studies
in relevant in vivo and in vitro settings. Moreover, we have
constructed an initial mathematical model of caspase activation and coupled it
to a model describing some of the reactions of NO• in hepatocytes. Our studies
suggest that modulation of iron, oxygen, and superoxide may dictate whether NO•
is hepatoprotective or hepatotoxic.
[Back to top]
The Role of iNOS
in Chronic Inflammatory Processes In Vivo: Is it Damage-Promoting,
Protective, or Active at all?
Christoph V. Suschek,
Oliver Schnorr and Victoria Kolb-Bachofen
The expression of the inducible nitric oxide
synthase (iNOS) is one of the direct consequences of an inflammatory process.
Early studies have focused on the potential toxicity of the ensuing high-output
NO-synthesis serving as a means to eliminate pathogens or tumor cells but also
contributing to local tissue destruction during chronic inflammation. More
recently, however, data are accumulating on a protective effect of high-output
NO synthesis and – equally important – on a generegulatory function that helps
to mount a protective stress response and simultaneously aids in downregulating
the proinflammatory response. These findings appear to contrast to the often
observed sustained iNOS-expression during chronic inflammatory diseases, as for
instance in Psoriasis vulgaris and other conditions with a chronic Th1-like
reactivity.
We here pose the question as to whether the
iNOS is really active in these diseases. We review the data accumulated on iNOS
expression in chronic diseases. We also report on the various factors that
potentially interfere with proper NO formation by the expressed enzyme. We also
highlight the recent findings of how, why and where evidences emerge that
impeded NO formation contributes to chronic disease processes and finally
present details on our current understanding of such abnormally low NO
synthesis and its contribution to the pathophysiological processes of the human
proinflammatory skin disease Psoriasis vulgaris.
[Back to top]
The Dichotomous Role
of Nitric Oxide in the Pathogenesis of Accelerated Atherosclerosis Associated
with Systemic Lupus Erythematosus
Marc C. Levesque and J. Brice Weinberg
Atherosclerosis is an inflammatory disorder,
and the inflammation associated with systemic lupus erythematosus (SLE)
accelerates the development of atherosclerosis. Nitric oxide (NO) is an
important mediator of inflammation including the inflammation associated with
atherosclerosis and SLE. Endothelial nitric oxide synthase (NOS3)-mediated
constitutive expression of NO promotes endothelial integrity and normal
vascular function. In contrast, inducible nitric oxide synthase- (NOS2)
mediated expression of NO promotes endothelial dysfunction and atherogenesis.
Statins appear to have anti-inflammatory properties and reverse many of the
deleterious effects associated with NO metabolism in atherosclerosis. Statins
augment NOS3 expression and inhibit the induction of NOS2. Therefore, the balance
between normal vascular function and atherogenesis may be mediated by
differences in the quantity, location, and timing of NO production within
vessel walls.
[Back to top]
Cross-Talk Between
Nitric Oxide and Transforming Growth Factor-b1 in Malaria
Yoram Vodovotz, Ruben
Zamora, Matthew J. Lieber and Shirley Luckhart
Malaria has re-emerged as a global health
problem, leading to an increased focus on the cellular and molecular biology of
the mosquito Anopheles and the parasite Plasmodium with the goal of
identifying novel points of intervention in the parasite life cycle.
Anti-parasite defenses mounted by both mammalian hosts and Anopheles can
suppress the growth of Plasmodium. Nonetheless, the parasite is able to
escape complete elimination in vivo, perhaps by thwarting or co-opting
these mechanisms for its own survival, as do numerous other pathogens. Among
the defense systems used by the mammalian host against Plasmodium is the
synthesis of nitric oxide (NO), catalyzed by an inducible NO synthase (iNOS).
Nitric oxide produced by the action of an inducible Anopheles stephensi
NO synthase (AsNOS) may be central to the anti-parasitic arsenal of this
mosquito. In mammals, iNOS can be modulated by members of the transforming
growth factor-b (TGF-b)
cytokine superfamily. Transforming growth factor-b is
produced as an inactive precursor that is activated following dissociation of
certain inhibitory proteins, a process that can be promoted by reaction
products of NO as well as by hemin. Ingestion by Anopheles of blood
containing Plasmodium initiates parasite development, blood digestion
which results in the accumulation of hematin (hemin) in the insect midgut, and
induction of both AsNOS and TGF-b-like
(As60A) gene expression in the midgut epithelium. Active mammalian TGF-b1 can be detected in the A. stephensi midgut
up to 48h postingestion and latent TGF-b1
can be activated by midgut components in vitro, a process that is
potentiated by NO and that may involve hematin. Further, mammalian TGF-b1 is perceived as a cytokine by A. stephensi
cells in vitro and can alter Plasmodium development in vivo.
Bloodfeeding by Anopheles, therefore, results in a juxtaposition of
evolutionarily conserved mosquito and mammalian TGF-b superfamily homologs that may influence
transmission dynamics of Plasmodium in endemic regions.