© 2000 American Heart Association, Inc.
Brief Reviews |
Interactions of Oxidants With Vascular Signaling Systems
From the Department of Physiology, New York Medical College, Valhalla.
Correspondence to Michael S. Wolin, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail mike wolin{at}nymc.eduwolin@nymc.edu
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Abstract |
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 Top Abstract IntroductionOxidant Species and Their...What Controls the Production...Relationships Between Cellular...Vascular Processes Regulated by...Concluding RemarksReferences |
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Abstract—Individual reactive oxygen species (ROS) and oxidation products of NO interact with vascular signaling mechanisms in ways that appear to have fundamental roles in the control of vascular physiological and pathophysiological function. The activities of ROS-producing systems (including various NADPH and NADH oxidases, xanthine oxidase, and NO synthase) in endothelium and/or vascular smooth muscle are controlled by receptor activation, oxygen tension, metabolic processes, and physiological forces associated with blood pressure and flow. This review focuses on how the chemical properties and metabolic sensing interactions of individual ROS (including superoxide anion, hydrogen peroxide, and peroxynitrite) interact with cellular regulatory systems to produce vascular responses. These species appear to often function through producing selective alterations in individual heme or thiol redox–regulated systems (including guanylate cyclase, cyclooxygenase, mitochondrial electron transport, and tyrosine phosphatases) to initiate physiological responses through signaling pathways that control phospholipases, protein kinases, ion channels, contractile proteins, and gene expression.
Key Words: oxidants • redox • signaling, vascular
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Introduction |
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TopAbstractIntroductionOxidant Species and Their...What Controls the Production...Relationships Between Cellular...Vascular Processes Regulated by...Concluding RemarksReferences |
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This review focuses on providing a logical rationale for the rather poorly understood mechanisms of how individual reactive oxygen species (ROS) interact with signaling systems of importance to vascular function. The interactions of oxygen and ROS with NO result in the generation of reactive nitrogen species (RNS), which possess additional oxidant signaling properties that need to be considered, because most individual ROS and RNS shown in the Figure
have unique ways of interacting
with cellular regulatory systems. There appear to be roles for oxidant
signaling in acute physiological processes, such as
the sensing of changes in PO2. As the
levels of key species increase, they often participate in the
activation of multiple types of pathophysiological
responses, such as the attenuation of vasodilator mechanisms mediated
through the stimulation of soluble guanylate cyclase (sGC)
and the promotion of adhesion protein expression or vascular
proliferative processes. When cellular antioxidant systems become
overwhelmed, oxidant species then become activators of
apoptotic or necrotic cellular injury. Thus, oxidant signaling
mechanisms are of importance in vascular biological processes ranging
from physiological responses to the alterations
observed in vascular diseases.1
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Oxidant Species and Their Potential Interactions With Signaling Systems |
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TopAbstractIntroductionOxidant Species and Their...What Controls the Production...Relationships Between Cellular...Vascular Processes Regulated by...Concluding RemarksReferences |
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Superoxide Anion
The production of ROS often begins with a 1-electron reduction of molecular oxygen to superoxide anion (O2·-) by various oxidases (Equation 1
),
which are discussed later in this article. Superoxide anion is a
negatively charged free radical that undergoes rather selective
chemical reactions with the components of biological
systems. Although O2·- reacts
with itself with a rate constant of 8x104
mol-s · L · s-1
to form H2O2 and
O2 (Equation 2), superoxide dismutase (SOD)
enzymes function to accelerate the removal of
O2·- as a result of their rate constant of
2x109 mol-1 · L ·
s-1 for the reaction with
O2·-.2
 | (1) |
 | (2) |
 | (3) |
Vascular tissue contains a cytosolic copper-zinc form of SOD
(CuZn-SOD), a mitochondrial manganese form of SOD (Mn-SOD), and an
extracellular CuZn-SOD. One of the most important roles of SOD is the
prevention of the reaction of O2·- with NO
shown in Equation 3
. It has been demonstrated that CuZn-SOD permits NO
release from the endothelium3 4 and
NO-mediated vascular smooth muscle (VSM) relaxation,4 5
whereas extracellular SOD appears to protect NO during its diffusion
from endothelium to VSM.6 The activities
of intracellular oxidases typically seen in vascular tissue should
result in levels of O2·- in the nanomolar
range in the absence of SOD, and the presence of SOD is likely to lower
O2·- concentrations into the
picomolar range. Picomolar levels of
O2·- are not likely to have
direct interactions with signaling mechanisms. However, these low
levels of O2·- can be a source, through
reactions associated with Equation 2, of concentrations of
H2O2 in the high
picomolar to low nanomolar range that interact with signaling systems.
Because O2·- reacts with NO
with a rate constant of 7x109
mol-1 · L· s-1, which is 3 times
the rate of its reaction with SOD, when the levels of NO increase into
the elevated nanomolar range and approach the local concentrations of
SOD, NO is able to compete with SOD for the scavenging of
O2·-.7 8 9
This results in the production of peroxynitrite
(ONOO-; see Equation 3) in amounts that can potentially
interact with regulatory systems that are of biological
significance.7 9 As the levels of
O2·- increase, it readily interacts with
iron-sulfur (Fe-S) centers at key cellular sites, including
mitochondrial aconitase, causing prolonged inhibition of mitochondrial
function.10 Superoxide also causes the release of iron,
and the liberated iron can potentially participate in signaling
processes through reduction to its ferrous (Fe2+)
form, which reacts with peroxide to form highly reactive "hydroxyl
radical"–like species ("·OH"), or it can promote oxidative
stress–associated tissue injury.11 When nanomolar levels
of O2·- are formed in the
extracellular environment in the absence of appreciable SOD activity,
it readily attenuates the actions of NO12 and vasoactive
catecholamines,13 including
norepinephrine, epinephrine, and the drug
isoproterenol. This occurs as a result of the direct chemical reactions
between O2·- and these vasoactive agents.
Some of the potential mechanisms through which
O2·- and other ROS interact with vascular
signaling systems are summarized in Table 1.
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H2O2 and Peroxide Metabolism
H2O2 is a relatively
stable species, with biological diffusion properties that are similar
to H2O. It is either derived from
O2·- through Equation 2, or it is directly
produced by certain oxidases through a 2-electron reduction of
O2. A biologically significant source of other peroxides
that interact with oxidant-related signaling systems are
lipoxygenase enzymes, which typically metabolize
arachidonic acid into hydroperoxyeicosatetraenoic acids
species.14 It appears that the most sensitive and
physiologically relevant mechanisms through
which the various peroxide species interact with signaling systems are
through processes linked to their metabolism by enzymes
with peroxidase-like activities.
Catalase metabolizes H2O2,
but not lipid peroxides, by initially reducing it to
H2O as a result of donating 2 electrons from its
ferric heme, forming a highly oxidized heme intermediate called
compound I (see Equation 4).15 The heme of compound I of
catalase is then reduced back to its ferric form by oxidizing a second
molecule of H2O2 to
O2 (see Equation 5). The rate constants for these
2 reactions result in the formation of compound I of catalase as
H2O2 levels approach 1
nmol/L. As the levels of
H2O2 increase, 
40% of
catalase exists as the compound I species.15 It has been
demonstrated that the activity of sGC is activated by peroxide
metabolism by catalase under conditions that are closely
associated with the formation of the compound I species.16
Evidence has accumulated that
H2O2 can produce vascular
relaxation by stimulating sGC through studies that (1) examined the
actions of agents that inhibit sGC stimulation by
H2O2 (methylene blue and
LY83583), (2) measured the association between changes in cGMP and
vascular relaxation, and (3) characterized the actions of probes that
inhibit H2O2
metabolism by catalase (3-amino-1,2,4-triazole, alcohols,
ebselen, O2· -, and NO).17 The
properties of stimulation of sGC by
H2O2 suggest that
its expression is likely to be modulated by competing processes,
including the efficiency of
H2O2 metabolism
by glutathione (GSH) peroxidase and by the levels of the
physiological modulators of peroxide
metabolism by catalase that inhibit sGC stimulation,
including O2·-, NO, and other tissue-derived
electron donors for compound I of catalase, which remain to be
identified.
 | (4) |
 | (5) |
GSH peroxidase metabolizes
H2O2 and other biological
peroxides by reducing them with the use of electrons derived from the
oxidation of GSH to its disulfide form (GSSG), as seen in Equation 6.
The product of this pathway, GSSG, has the potential to regulate
signaling systems (see Thiol Oxidation and Nitrosation) through
promoting the S-thiolation (RSSG) of key protein thiols
(RSH), as seen in Equation 7, because as the formation of GSSG
increases, it appears to be used to form S-thiolated
proteins.18 S-Thiolation can also promote
disulfide formation [R(S-S)] with adjacent protein thiols when they
are present.
 | (6) |
 | (7) |
Heme peroxidases present in tissues are additional enzymes with very high rates of reaction with peroxides. In mammalian systems, the metabolism of peroxide by these enzymes is often linked to the formation of signaling molecules, such as prostaglandins (PGs) by cyclooxygenase (COX) or the generation of additional ROS by myeloperoxidase. COX has an unusual mechanism of activation by peroxides, which seems to involve oxidizing its heme to a form that catalyzes the generation of PGs, and a peroxide produced by the COX reaction (PGG2) appears to help sustain the production of PGH2 by this enzyme.19 The availability of peroxide for metabolism by COX appears to be one of the most important mechanisms that control the biosynthesis of PGs by tissues.20 Certain biological lipid peroxides have much more efficient interactions with COX than does H2O2.
Peroxide-derived ROS, often described as species with hydroxyl radical
(·OH)-like reactivity, may also be involved in signaling processes.
Peroxides readily react with transition metals present in
biological systems, such as iron, and this can result in the formation
of species that are involved in signaling or tissue injury processes.
The phagocytic cell myeloperoxidase metabolizes
H2O2 to hypochlorous acid
(HOCl), which can react with amines (eg, RNH2) to
form chloramines (eg, RNHCl). Although the myeloperoxidase-derived
HOCl- and RNHCl-type species readily react with thiols and although
chloramines appear to have significant biological
activity,21 it is not yet known whether these actions are
linked to the control of signaling mechanisms in a manner that is
independent of the cytotoxic actions of these species. Myeloperoxidase
is also able to form RNS with tyrosine-nitrating activity when both
nitrite and H2O2 are
present.22 The reaction of
H2O2 with ferrous iron
(Equation 8) results in the formation of ·OH. Although the extremely
high rate of reaction of ·OH with most molecules in biological
systems has resulted in much debate regarding its hypothesized role in
signaling processes, there is substantial evidence suggesting that the
reaction of peroxides with Fe2+ bound to proteins
or small molecular weight molecules can result in stabilized iron-bound
species with ·OH-like reactivity.11 These "·OH"
species appear to have a much greater potential for catalyzing
reactions that could be involved in signaling processes; eg, one could
speculate that a reaction catalyzed by a specific "·OH" or an
enzyme-bound species with ·OH-like reactivity could be involved the
selective oxidation of a key site on a protein involved in activation
of a signaling process.
 | (8) |
NO and RNS
The most significant interactions of NO with signaling systems
involve its reaction with ferrous heme groups, certain other metal
sites, and free radical species. Formation of RNS through the oxidation
of NO or through its reaction with ROS appears to result in the
production of species that have additional interactions with
regulatory processes. The most potent actions of NO occur over the
lower nanomolar concentration range, and they include binding to the
heme groups of sGC and heme-copper complexes of cytochrome oxidase. The
selective actions of NO with these proteins appear to originate from
their rates of binding NO, which are in the range of
108 mol · L-1 ·
s-1.23 24 This results in a stimulation
of the production of cGMP (associated with processes including
vasodilation and the inhibition of platelet aggregation and
neutrophil adhesion to the endothelium) and a
reversible inhibition of mitochondrial respiration (associated with an
improvement of the efficiency of energy metabolism). At
these low levels of NO, the reaction of NO with
O2·- leads to an attenuation of the
stimulation of sGC12 and a conversion of the reversible
inhibition of respiration to what appears to be a prolonged, and
perhaps irreversible, inhibition of respiration25
resulting from the release of iron from Fe-S sites other than
cytochrome oxidase.26 Although
O2·- is known to cause an irreversible
inhibition of respiration by damaging the Fe-S center of the Krebs’
cycle enzyme aconitase,10 it appears that the interaction
with NO enhances the potency of O2·- as
an inhibitor of respiration.25 Thus, the
interaction of NO with O2·- seems to
attenuate processes thought to be associated with the beneficial
signaling actions of NO.
When NO concentrations increase into the range of the tissue levels of SOD, NO competes with SOD for the removal of O2·- by forming ONOO-. Nitrogen dioxide (NO2) appears to be produced in significant amounts from ONOO-. Significant amounts of NO2 may also be formed from the H2O2-dependent myeloperoxidase reaction in the presence of low micromolar levels of the NO decomposition product nitrite22 and from the reaction of O2 with NO levels in the high nanomolar range or greater.27 The latter reaction could potentially occur in membranes because of the greater solubility of NO and O2 in hydrophobic environments.27 As the levels of ONOO- and RNS increase, these species have signaling effects on tissue function that are of potential physiological significance. The most potent effects of ONOO- and RNS appear to be thiol modifications that either affect the function of signaling systems or result in the production of tissue-derived donors of NO. Oxidized NO-derived species, including ONOO-, NO2, and N2O3, readily interact with GSH and other thiols in tissues to cause thiol oxidation or the formation of nitrated (RSNO2) or nitrosated (RSNO) thiols.7 8 9 28 29 It appears that the modification by RNS of key thiols on proteins that possess regulatory functions can serve as a site of control of signaling (see Thiol Oxidation and Nitrosation). The most abundant of the RSNOx species are also likely to function as tissue storage forms and donors of NO. When iron is reductively released from tissue storage sites, such as ferritin, and from damaged Fe-S centers, it also has the potential to participate in the formation of NO donors through the generation of (RS)2Fe(NO)2 complexes.30 High levels of ONOO- also seem to form NO donors through the modification of alcohols and sugars to nitrated species, which release NO in the presence of thiols.31 Thus, the formation of RNS seems to be an important process in the interaction of oxidants with signaling systems.
RNS may also participate in cellular signaling processes through
additional interactions with lipids (see Eicosanoids and PLs) and
proteins. Certain key metabolic enzymes, including the Fe-S
centers of the mitochondrial electron transport chain and aconitase,
and thiols located on glyceraldehyde-3-phosphate
dehydrogenase32 and creatine kinase33 appear
to be readily modified by ONOO- and related RNS
species. Some of these modifications could affect tissue function
through altering the pathways and efficiency of energy
metabolism in a manner that influences a signaling process,
such as ATP-dependent potassium channels. The formation of
ONOO- is associated with the inhibition of several key
antioxidant systems, including catalase,9 GSH
peroxidase,34 and the mitochondrial SOD or
Mn-SOD,35 and these actions of RNS could function to
enhance oxidant signaling or injury-associated processes.
ONOO- and NO2 cause the nitration of tyrosine
groups on proteins. CuZn-SOD35 and carbon
dioxide36 appear to enhance the rates of certain
ONOO--mediated tyrosine nitration reactions. A
tyrosine group on PGI2 synthase appears to
be particularly sensitive to nitration by ONOO-,
resulting in inactivation of this enzyme.37 Tables 1 and 2 list many of the known
metabolic and signaling systems that are potentially
regulated by ONOO- and related RNS species.
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Thiol Oxidation and Nitrosation
Protein thiols seem to have markedly different sensitivities to
modification by S-thiolation or thiol oxidation and
nitrosation. Thus, the degree of oxidation of GSH to GSSG caused by the
metabolism of peroxides, oxidants, or nitrosative stress
may have a major influence on which systems are modulated by the redox
status of GSH. It is likely that certain thiols will be very sensitive
to chemical or enzymatic S-thiolation and that other protein
thiols will only be modified at much higher levels of oxidant stress.
As the levels of GSSG increase, its metabolism by GSH
reductase will decrease the levels of NADPH, a cofactor that is
potentially involved in the reduction of modified thiols through
thioredoxin reductase and related systems18 (see
Interactions Between Redox Control Mechanisms and Oxidant Signaling).
Table 2 includes some of the potential linkages between proteins
regulated by thiol redox and signaling mechanisms (discussed later in
this article) that appear to be controlled by rather poorly understood
thiol redox–related processes.
Thiols on proteins may also be directly modified by ROS and RNS to form
oxidized species [RSSG, R(S-S), and RSOx] or
nitrosated species (RSNOx) through reactions such
as those included in Equations 9 through 16.28 38 39 40 Each
thiol group is likely to have its own unique sensitivity and chemical
reactivity properties to modification by ROS or RNS that is determined
by the surrounding environment. These properties are likely to define
the conditions under which a signaling system is selectively influenced
by individual oxidant species. The actual rates of reactions of
peroxides with thiols are generally rather slow.38
However, efficient modifications to oxidized thiols [RSSG, R(S-S), and
RSOx] can potentially result from activation of
the thiol group by interactions within the protein environment in which
they are located and by peroxides being converted through metal
chelation to more reactive "·OH." In addition to the formation of
the RSNOx species (see NO and RNS), RNS can
promote the generation of oxidized thiols [RSSG, R(S-S), and
RSOx] and increased levels of GSSG. Disulfide
[R(S-S) and RSSG] and sulfenic acid (RSOH) modifications are
oxidized forms of thiols that can be readily reduced back to the
original sulfhydryl by thiols, other reducing agents, or protein redox
systems. In contrast, further oxidation to sulfinic
(RSO2) or sulfonic (RSO3)
oxidation states is likely to result in an irreversible modification of
the protein.39 Although nitrosated low molecular weight
thiols (eg, GSNO) can also promote the formation of nitrosated or
oxidized thiols on proteins through transfer of the NO group to protein
thiols (transnitrosation), this process is more likely to occur in the
extracellular environment, because it is inhibited by cellular levels
of GSH.40 Thus, modifications of protein thiols to
RSNOx, RSOH, R(S-S), and RSSG forms can
potentially be part of signaling mechanisms controlled by individual
ROS and RNS species because of the potential for reversibility and the
fine-tuned control of these processes by the function of cellular redox
systems. Certain tyrosine phosphatases,41 potassium
channels,42 and the G protein
p21ras43 appear to have readily oxidized
or nitrosated thiol groups that seem to control the function of these
proteins, which have prominent roles in activating cellular signaling
systems.
 | (9) |
 | (10) |
 | (11) |
 | (12) |
 | (13) |
 | (14) |
 | (15) |
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Interactions Between Redox Control Mechanisms and Oxidant
Signaling
The various cell types in the vessel wall contain the redox
systems that are typically seen in other cell types. However, the
ability of a cell to maintain the normal redox status of a particular
redox system is likely to be an important factor in the control of
oxidant signaling systems. Although many aspects of the function of
redox systems remain poorly understood, certain facets of the redox
status of cytosolic NADP(H), NAD(H), and GSH suggest that the redox
status of these systems is a major contributor to the processes that
influence the expression of oxidant-linked signaling mechanisms. It is
currently thought that the pentose phosphate pathway of glucose
metabolism is a major contributor to maintaining the
majority of NADP(H) in its reduced form. NADPH-dependent GSH reductases
are thought to be the major enzyme systems that maintain GSH in its
reduced form. As GSH oxidizes to GSSG during the metabolism
of peroxide or as a result of its interaction with reactive species,
the increased level of GSSG appears to result in a substantial increase
in proteins that have been S-thiolated with
GSH.44 Thioredoxin reductase and related enzymes are
thought to have a significant role in restoring the normal thiol redox
status of proteins, and the function of this system appears to be
dependent on the redox status of NADP(H), a reducing cofactor used by
this system.18 In addition to the influence of NADPH and
GSH redox systems on
H2O2-elicited stimulation
of sGC,17 NADPH-linked oxidoreductase systems appear to
prevent the expression of additional inhibitory mechanisms
involving oxidation of the heme and/or thiols on sGC.45
Thus, the redox status of NADP(H) and GSH is likely to have a major
influence on the expression of multiple oxidant-associated signaling
mechanisms.
It is currently thought that the balance between the generation of NADH
by glyceraldehyde-3-phosphate dehydrogenase and the
removal of cytosolic NAD(H) by the functioning of mitochondrial shuttle
systems and the lactate dehydrogenase reaction has a major influence on
the redox status of cytosolic NAD(H), keeping it primarily in the form
of NAD.17 46 47 Glucose metabolism by the
sorbitol pathway could be an additional source of cytosolic NADH under
hyperglycemic conditions.47 Recent
studies17 46 have provided evidence that the levels of
cytosolic NADH appear to control the activity of an
O2·--producing NADH oxidase [see NAD(P)H
Oxidases]. Within mitochondria, the redox status of NAD(H) is thought
to be determined by the balance between the availability of substrates
for the Krebs’ cycle and the usage of NADH by the electron transport
chain. The levels of intracellular calcium,
PO2, ADP, pH, NO, and
other factors that influence mitochondrial membrane potential seem to
function together to determine the redox status of mitochondrial
NAD(H), whereas the redox status of components of the electron
transport chain appear to control mitochondrial
O2·- production (see Mitochondrial
Systems). The redox status of mitochondrial NADP(H) seems to be
controlled by a balance between its generation from NADH by the
transhydrogenase reaction and its use by systems such as the GSH
reductase reaction. Although little is known about the importance of
intramitochondrial ROS signaling mechanisms, it is likely that NADP(H)
and GSH redox would have a major influence over processes involving
changes in mitochondrial thiol redox. The redox status and/or the
availability of other antioxidant-associated systems becomes important
when the levels of ROS and RNS result in the generation of additional
free radicals or highly reactive oxidized metal species. Agents such
as 
-tocopherol, urate, various thiols,
ascorbate, and perhaps other radical scavengers, including NO, appear
to quench these reactive species in a manner that prevents their
destructive actions. Thus, various biological redox systems have a
major influence on controlling the production, levels, and
function of signaling systems influenced by certain ROS and RNS. As the
capacity of redox systems to control the levels of reactive species is
exceeded, free radical–scavenging antioxidants function either to
inactivate these reactive species or to scavenge the free
radicals that they generate.
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What Controls the Production of ROS and Their Actions on Signaling Systems? |
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TopAbstractIntroductionOxidant Species and Their...What Controls the Production...Relationships Between Cellular...Vascular Processes Regulated by...Concluding RemarksReferences |
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This section discusses the processes that control ROS production by many of the better understood oxidases (see Table 3
) as well as aspects of the function of
metabolizing systems for these species that influence the interaction
of ROS and RNS with signaling systems. The production and
metabolism of ROS are highly compartmentalized. For
example, the cytosol, mitochondria, peroxisomes, and extracellular
region appear to function as environments whose production and
metabolism of ROS generally appear to be rather independent
of each other.15
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Control of the Production of Oxidant Species
It is important to keep in mind that each active source of
production of ROS within a compartment contributes to the local
levels of each species and that transport of individual ROS across
compartments is often possible when the capacity of the scavenging
systems is exceeded.
NAD(P)H Oxidases
There are several known NAD(P)H oxidases. Phagocytic cells have a
membrane-bound flavohemoprotein containing NADPH oxidase with
cytochrome b558, which produces minimal
amounts of O2·- until it is stimulated by
signaling processes associated with cellular activation. The
membrane-bound gp91phox and p21phox
subunits are thought to contain the flavoprotein and heme sites, and
p47phox, p67phox,
p40phox, and the G protein rac-2 appear to bind
the membrane-bound subunits on cellular activation.48
This binding is associated with the generation of a highly active NADPH
oxidase capable of producing large amounts of
O2·- on the external surface of the plasma
membrane. Although many of the subunits of this NADPH oxidase appear to
be present in vascular endothelium and
VSM,49 50 51 52 53 54 55 56 57 58 it is not yet known whether these subunits are
regulated and function in a manner similar to the phagocytic cell
oxidase. Thus, NADPH oxidase is an important source of ROS in segments
of the circulation that are exposed to activated inflammatory
cells.
A somewhat similar NAD(P)H oxidase was identified in
endothelium49 and VSM.50 51
This oxidase appears to have a basal NAD(P)H-dependent
O2·--generating activity in the absence of
cellular activation, and certain stimuli, such as
angiotensin II,51 tumor necrosis
factor-,52 thrombin,53 and
lactosylceramide,54 appear to stimulate the activity
and/or expression of this protein. Although there is evidence that
endothelium55 and
VSM50 51 52 53 56 57 58 contain many of the components analogous
to the p21, p47, p67, and gp91 subunits of the phagocytic oxidase, the
role of most of these proteins in the regulation of the vascular
NAD(P)H oxidase requires further study. It has recently been reported
that the vascular NAD(P)H oxidase has a mox-1 (or
p65mox) subunit that (on the basis of sequence
homology) appears to be analogous to the p91phox
subunit of the phagocytic oxidase.57 In human aortic VSM
cells, activation of NAD(P)H oxidase by thrombin is associated with
increased expression and membrane binding of
p47phox and rac-2.53
Angiotensin II was also observed to cause membrane binding
of p47phox in bovine pulmonary arteries
under conditions that increased NADH oxidase activity.56
Expression of the p21phox and mox-1 subunits is
observed to be associated with O2·-
generation and growth in VSM cells.51 57 Studies in bovine
pulmonary and coronary arterial smooth
muscle and coronary artery endothelial cells
have provided evidence that a potentially important control mechanism
for NADH oxidase activity appears to be the availability of cytosolic
NADH (see Interactions Between Redox Control Mechanisms and Oxidant
Signaling).17 46 49 50 59 The rate of
O2·- production by the bovine VSM
NADH oxidase seems to be dependent on the concentration of
O2 in a manner that permits this oxidase to function as a
physiological PO2
sensor.17 50 Thus, NAD(P)H oxidases may be a key source of
ROS that participate in vascular oxidant–related signaling mechanisms
under physiological and
pathophysiological conditions.
There are additional NAD(P)H oxidases that may contribute to vascular ROS signaling. Cytochrome P-450 is known to be a source of O2·- production through its NADPH oxidase activity. The primary cytochrome P-450–type enzyme observed to be a significant source of ROS in the vessel wall is the endothelial form of NO synthase (NOS). The various forms of NOS have NADPH oxidase activity. It has been demonstrated that this activity is markedly enhanced in endothelium as a result of a deficiency of its cofactor tetrahydrobiopterin60 and also as a result of exposure to atherogenic levels of LDL.61 COX is an additional source of O2·- production during the synthesizing of PGs or metabolizing of peroxides because of its ability to co-oxidize substances such as NAD(P)H.62 COX has been observed to be a significant source of O2·- in the cerebral circulation.63 Thus, various pathophysiological conditions seem to be associated with specific NAD(P)H oxidases becoming significant vascular sources of ROS.
Xanthine Oxidase
The xanthine dehydrogenase activity present in vascular
endothelium is readily converted into xanthine oxidase
by processes including thiol oxidation and/or
proteolysis.64 Xanthine oxidase metabolizes hypoxanthine,
xanthine, and NADH to form O2·- and
H2O2. Ischemia and hypoxia are
conditions that promote the accumulation of these substrates for ROS
production and the increases in xanthine oxidase activity.
Xanthine oxidase appears to be an important source of ROS
production in ischemia/reperfusion64 65
and hypercholesterolemia.66 Thus,
xanthine oxidase has the potential to be an important source of ROS
production under certain pathophysiological
conditions.
Mitochondrial Systems
The significance of the production of ROS by mitochondria
in vascular signaling is rather poorly understood. Mitochondria are
thought to produce O2·- from the semiquinone
form of coenzyme Q and a reduced component of NADH
dehydrogenase.67 It appears that inhibition of
mitochondrial respiration by NO can result in increases in
mitochondrial ROS production.67 On the basis of
the actions of rotenone, it has been suggested68 that
mitochondrially derived ROS influence hypoxic pulmonary
vasoconstriction (see Roles for Oxidant Signaling and Vascular
O2-Sensing Mechanisms). Mitochondrially derived ROS could
also be important contributors to the expression of
apoptosis.
Antioxidant and Metabolic Control of ROS Levels
and Actions
The influence of metabolizing or scavenging systems on the levels
individual ROS (and RNS) may be a key aspect that determines the
expression of signaling processes regulated by these species. This
article has already considered the roles of SOD, catalase, and GSH
peroxidase in controlling the levels of O2·-
and peroxides, the interaction of O2·- with
NO, and the ways through which peroxide metabolizing enzymes interact
with sGC, thiol redox–linked signaling, and PG biosynthesis. The
expression of these ROS-scavenging systems appears to be highly
regulated by environmental factors, such as previous exposure to
oxidant stress. In addition, as considered in Interactions Between
Redox Control Mechanisms and Oxidant Signaling, certain key cellular
redox systems have a major influence on the function of signaling
processes activated by ROS.
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Relationships Between Cellular Control Mechanisms Regulated by ROS and Interactions of ROS With Signaling Systems |
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TopAbstractIntroductionOxidant Species and Their...What Controls the Production...Relationships Between Cellular...Vascular Processes Regulated by...Concluding RemarksReferences |
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This section focuses on discussing the manner through which ROS and RNS interact with some of the vascular control systems that appear to be regulated by redox-associated processes.
Ion Transport Systems
Reports that elevated levels of
H2O2 cause
calcium-dependent release of NO from the
endothelium69 70 and potassium
channel–dependent relaxation of VSM68 71 stem from
observations demonstrating the potential importance of oxidant
regulation of ion transport mechanisms. Although the actual links
between ROS or RNS and the function of cellular ion transport systems
are generally not well understood, evidence exists for the potential
importance of several processes. The mechanisms that control the uptake
and/or release of sarcoplasmic reticulum or microsomal calcium in
VSM72 and endothelium73
appear to be rather sensitive to oxidants. The oxidation of thiols that
control the activities of these ion transport systems has often been
considered to be a mechanism of regulation. Plasma membrane potassium
channels in VSM that control a
hyperpolarization-elicited relaxation appear to be
opened by mechanisms associated with thiol oxidation by
ROS68 or thiol modification by RNS.42
Calcium-regulated potassium channels appear to mediate the vasodilation
to H2O2 in the rat cerebral
microcirculation. Interestingly, in the cat cerebral microcirculation,
O2·- was reported to produce dilation
by calcium-dependent potassium channels, whereas
H2O2 and
ONOO- appeared to cause dilation through the opening
of ATP-dependent potassium channels.74 Other signaling
systems that are regulated by oxidants, such as cGMP-dependent
processes, also control the function of ion channels. A recent study of
the mechanism of relaxation of endothelium-removed
bovine coronary arteries to diamide, an oxidant of GSH and
adjacent protein thiols, has provided evidence for a mechanism
involving the inhibition of plasma membrane calcium
influx.75 In addition, the mechanism of relaxation of
these arteries to diamide does not appear to involve modulation of sGC,
potassium channels, O2-dependent processes, or signaling
systems associated with the release of intracellular calcium or
contraction elicited by protein kinase C (PKC).59 75 Thus,
vascular ion channels are potentially controlled by multiple
redox-linked mechanisms, and this is likely to be responsible for the
diversity of observations that have been made.
Protein Phosphorylation
The function of multiple components of protein
phosphorylation systems has been shown to be altered by
ROS and RNS. It is important to emphasize that a specific
phosphorylation could be controlled by interactions of
ROS or RNS with an independent signaling system (eg, calcium, cGMP, or
diacylglycerol) that influences the function of the protein kinase
catalyzing the phosphorylation or the activity of a
phosphatase that removes the phosphate group. For example, signaling
through cGMP-dependent protein kinases is likely to be highly regulated
by the status of ROS, RNS, and redox systems because of their influence
on the activity of sGC. Tyrosine-specific protein phosphatases have
been demonstrated to have an essential thiol at their catalytic site,
and modification of this thiol by either ROS or RNS is a potentially
important biological mechanism that inhibits these
proteins.41 76 The stimulation of tyrosine
phosphorylation by
H2O2 has been reported to
be a mechanism of activating most forms of PKC, and enzyme activation
seems to be independent of diacylglycerol generation.77
Evidence is emerging that redox processes markedly influence the
balance of the activities between the various mitogen-activated
protein kinase (MAPK) systems that appear to regulate vascular force
generation,78 proliferation,79 and adaptive
responses to injury.80 The function of the extracellular
signal–regulated kinases, including p42/p44 MAPK,
stress-activated or c-Jun N-terminal kinase, and the p38
MAPK–associated pathways, all seem to be significantly influenced by
redox processes.79 80 It has been recently reported that
the angiotensin II receptor and
H2O2 can also
activate protein kinase B by a phosphatidylinositol
3-kinase–dependent mechanism.81 Some of the sites with
which ROS and RNS potentially interact in the control of MAPK systems
appear to be tyrosine phosphatases, the small molecular weight G
protein p21ras, PKC, and sGC. The impact of
inhibition of tyrosine phosphatases by thiol redox processes would be
to cause an apparent enhancement of upstream protein kinase–linked
signaling systems that are partially activated under
physiological or
pathophysiological conditions.82 In
addition, there is evidence that oxidant mechanisms may stimulate
increases in the autophosphorylation of receptor-linked
tyrosine kinases that activate the MAPK
pathways,83 and
H2O2 has been observed to
stimulate tyrosine phosphorylation of the epidermal
growth factor receptor in VSM cells,84 whereas nitrosation
of a thiol on p21ras stimulates the activation of
p42/p44 MAPK.43 One area that is very poorly understood is
how individual ROS and RNS influence the balance between the activities
of the MAPK pathways. For example, the simultaneous
activation of p21ras and PKC are potentially key
processes that stimulate the p42/p44 MAPK pathway via activation of Raf
in VSM.79 80 A phosphorylation mediated by
cGMP-dependent protein kinase has also been demonstrated to
activate the p42/p44 MAPK pathway in VSM.85
Interestingly, the p42/p44 MAPK pathway may mediate a
receptor-stimulated calcium-independent contractile response in VSM
through the phosphorylation of
caldesmon.86 This field seems to be extremely important
because of its apparent role in influencing adaptive responses of the
vessel wall to altered physiological states and
injury. Thus, ROS and RNS have multiple ways of interacting with
processes that control the expression of responses linked to the
various protein phosphorylation systems that are
normally part of receptor-regulated signaling systems. Because the
inhibition of tyrosine phosphatases is often a key process through
which oxidants interact with protein
phosphorylation–linked signaling systems, the basal
activities of these signaling systems under
physiological conditions and the extent to which
individual ROS and RNS influence these signaling systems are likely to
be key factors in determining the observed vascular responses.
Eicosanoids and PLs
H2O2 has been reported
to stimulate multiple forms of vascular phospholipases (PLs), including
PLA2, PLC, and PLD,87 88 and ROS and
RNS modulate the activity of arachidonic
acid–metabolizing enzymes and directly modify lipids to species that
are vasoactive. The signaling pathways through which ROS control the
activity of PLs are rather poorly understood. Cytosolic
PLA2 activity appears to be stimulated by
H2O2 through a tyrosine
kinase–dependent pathway,88 potentially involving the
phosphorylation of PLA2 by the
activation of MAPK and PKC.87 There is evidence that
tyrosine phosphorylation also contributes to the
peroxide-mediated stimulation of PLC and PLD,88 and PKC is
potentially an important participant in the activation of
PLD.89 Activities of the
lipoxygenase14 and the previously
discussed COX20 enzymes are stimulated by low levels of
peroxides, and peroxynitrite appears to stimulate COX in a manner
similar to that of peroxides.90 Elevated levels of
peroxides appear to inactivate COX and
PGI2 synthase, and PGI2
synthase is also inactivated by
pathophysiological levels of
ONOO-.37 Thus, oxidants are potent
stimuli in the activation of PLs and the generation of certain
eicosanoids. Oxidative or nitrosative stress appears to alter the
metabolites formed in a manner that reduces the generally beneficial
effects of PGI2 while increasing the
levels of metabolites such as PGH2, which may
contribute to pathophysiological responses,
including thrombosis and vasoconstriction.37
Products derived from direct chemical reactions between ROS or RNS
and lipids may also generate lipid-derived species with biological
activity. As a result of its antioxidant activity, NO can add to lipid
radicals (L· , LO· , and LOO·) to form lipid NO-containing
species by the reactions shown in Equation 17.91 Although
little is known about the biological activities of these NO-containing
lipids, they are likely to function as tissue storage forms of NO. One
of the products of the reaction of ONOO- with
arachidonic acid appears to be
-hydroxynitro–containing eicosanoids
[R-C(OH)-C(NO2·-R'], which spontaneously release NO and
cause vascular relaxation.92 Several of the metabolites
considered to be indicators of lipid peroxidation, including
isoprostanes93 and 4-hydroxy-2-nonenal,94
have been shown to have biological activities. Chemical interactions
between lipids and ROS or RNS appear to generate species that
potentially have signaling actions that influence vascular function,
yet the actual roles of these species remain to be defined.
 | (17) |
Gene Expression
Redox processes that are influenced by ROS and RNS appear to have
a major role in modulating gene and protein expression through the
regulation of transcription factors (eg, nuclear factor-
B and
activator protein-1) and many additional mechanisms, which
have been considered in a recent review.80 Although this
field is beyond the scope of the present article, many important
aspects of ROS signaling can potentially be markedly altered through
changes in gene expression. For example, redox signaling regulates the
expression of (1) adhesion proteins that control inflammatory cell
recruitment, (2) antioxidant enzymes that control all aspects of ROS
interactions with signaling systems, (3) NOS, (4) receptors, and
perhaps (5) many respiratory adaptations to hypoxic environments. Thus,
the modulation of protein and gene expression by ROS and RNS also
appears to be an important aspect of the behavior of the signaling
systems these species regulate.
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Vascular Processes Regulated by ROS Signaling Systems |
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TopAbstractIntroductionOxidant Species and Their...What Controls the Production...Relationships Between Cellular...Vascular Processes Regulated by...Concluding RemarksReferences |
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There is rapidly growing literature on the effects or role of ROS and RNS on signaling systems. This section considers how the fundamental interactions of ROS with signaling systems are potentially linked to some of the better understood vascular biological processes that are known to be regulated by ROS.
Roles for Oxidant Signaling and Vascular
O2-Sensing Mechanisms
One of the first vascular responses suggested to be mediated
through oxidant signaling mechanisms was the contractile response of
the pulmonary vasculature to
hypoxia.16 17 68 95 At least 2 hypotheses
involving ROS are being actively considered for the mechanism of this
response. Both mechanisms share the concept that hypoxia is
removing a dilator mechanism controlled by ROS. Weir and
colleagues68 95 have suggested that mitochondrial and
cytosolic oxidases in pulmonary arterial smooth
muscle are controlling the redox status of key thiols on plasma
membrane voltage–regulated potassium channels through diffusible
cytosolic redox cofactors. Normoxia maintains the channels in an open
state, causing decreased force generation through
hyperpolarization by oxidizing thiols on the
channels.68 95 Our group has hypothesized that
H2O2 derived from
O2·- produced by an NADH oxidase, whose
activity is controlled by cytosolic NAD(H) redox and
PO2, decreases force
generation under normoxia. This is a result of the stimulation of cGMP
production by sGC being activated by the
metabolism of
H2O2 by
catalase.16 17 50 PGs are often observed to be mediators
of vascular responses caused by changes in
PO2.17 Stimulation of
the production of either dilator96 or
constrictor97 PGs by increases in
H2O2 under conditions such
as posthypoxic reoxygenation has been suggested to
mediate some of the responses that are observed. After inhibition of
the PG-mediated responses, these vascular segments show
H2O2-elicited responses
that appear to be mediated through the stimulation of sGC. Gestational
diabetes appears to enhance the
H2O2-elicited PG-mediated
contractile responses by a mechanism that seems to involve an
attenuated expression of the simultaneous
H2O2-elicited stimulation
of sGC through a process that may involve the inhibition of catalase
activity by increased levels of NO production.97
Because vascular oxidases, such as NADH oxidase,17 50 show
changes of rates of ROS production at
physiologically relevant
O2 tensions, these systems are likely to function
as vascular O2 sensors that activate
signaling mechanisms involved in
PO2-elicited changes in force and
perhaps environmental adaptations involving gene expression and
proliferation.
Potential Roles for Oxidant Signaling in Vascular Responses to
Receptor Agonists, Pressure, and Flow
Some of the responses to other physiological
processes, such as receptor activation, pressure, and flow, may involve
ROS-mediated signaling. It was initially observed in the cerebral
circulation that activation of bradykinin receptors and acute
elevations in pressure stimulated an increased production of
extracellular free radicals, such as
O2·-.63 COX activity in
the endothelium appeared to be the primary source of
these radicals. Subsequent studies identified multiple roles for
oxidant signaling in vascular regulatory processes. This section
emphasizes examples of roles for intracellular oxidant signaling
mechanisms that appear to link physiological
stimuli to some of the alterations that seem to occur in vascular
function.
Receptors and Vascular Proliferative Signaling
The growth-promoting agent angiotensin II was observed
to increase the activity of NAD(P)H oxidase activity in
VSM.51 Further studies on the oxidant-mediated
growth-promoting actions of angiotensin II in VSM cells
have identified what appear to be essential roles for
H2O2, the activation of
protein kinase B, PKC, and the p42/p44 MAPK systems.79 81
Other vascular growth-promoting agents, including
serotonin, have been demonstrated to stimulate the
formation of oxidants and activate
phosphorylation of p42/p44 MAP kinase.98
The potential mechanisms through which ROS interact with these protein
kinase–linked pathways is discussed in Protein
Phosphorylation.
Flow, Shear, and Stretch as an Initial Stimulus for
Endothelial Oxidant Signaling and Subsequent
Alterations in NO Regulation
Flow was also shown to be a stimulus for the production of
free radicals from the endothelium of intact vascular
tissue.99 Studies on the effects of flow on cultured human
umbilical vein endothelium100 have
identified the initial activation of NADH oxidase activity and a
subsequent increase in CuZn-SOD expression by exposure to steady
laminar shear. In this system, oscillatory stretching or shear stress
caused a sustained activation of pro-oxidant processes associated with
redox-sensitive gene expression. In a bovine aortic
endothelium cyclic stretching strain-type model, it was
observed (with the use of dominant-positive and -negative mutant cell
lines) that this stimulus activated the
p21ras-Raf-p42/p44 MAPK pathway through the
production of
H2O2.101 When
subjected to laminar shear stress, cultured bovine aortic
endothelium also shows evidence of increased oxidant
signaling involving activation of the c-Jun N-terminal kinase pathway
by ONOO-,102 and this may occur as a
result of the upregulation of NOS.103 Although shear
stress appears to increase endothelial cell NOS
expression through mechanisms that seem to be independent of the
actions of ROS, H2O2
has been reported to increase the expression of NOS by processes
associated with increased transcription and mRNA
stability.104 Although the actual mechanisms through which
the forces associated with changes in blood flow influence the
production of oxidant species is not known, alterations in
signaling mechanisms activated by ROS and RNS could participate
in the adaptation of vascular responses through changes in the
expression of proteins that modulate redox signaling, such as
increasing the expression of SOD.100 Thus, the shear
forces caused by blood flow can influence endothelial
signaling mechanisms and gene expression through changes in ROS and RNS
production. These processes may participate in adaptations of
vascular function to stimuli such as exercise.
Pressure or Wall Stress as a Stimulus for Oxidant
Signaling
The initial effects of pressure on vascular tissue appear to be
the release of O2·- from
endothelium-derived sources.63 For
example, exposure of isolated rat skeletal muscle arterioles to
elevated luminal pressure was observed to cause an
O2·--mediated attenuation of
endothelium-dependent relaxation.105 An
endothelium-independent contractile response of
isolated cat cerebral arteries to increases in flow has recently been
reported to be altered by probes that suggest a role for cell surface
integrins, O2·-, and tyrosine kinases in the
mechanism of this response.106 Thus, oxidant signaling is
potentially important in the acute responses of vascular tissue to
increases in pressure or wall stress.
Oxidant Signaling and Pathophysiological
Aspects of Endothelial-Vascular Function
There appear to be multiple ways through which
pathophysiological conditions in the vasculature
can promote the activation of oxidant signaling mechanisms. Some of the
better understood roles for these mechanisms in vascular
pathophysiology are briefly highlighted here.
Origins of Alterations in Endothelial
Oxidant-NO Signaling
Some of the stimuli for alterations in oxidant-NO signaling were
considered in Roles for Oxidant Signaling and Vascular
O2-Sensing Mechanisms and Potential Roles for
Oxidant Signaling in Vascular Responses to Receptor Agonists, Pressure,
and Flow. The vascular endothelium appears to have
multiple potential sources of ROS production, including
xanthine oxidase, NAD(P)H oxidases (including NOS, other cytochrome
P-450s, and p21phox-cytochrome
b558–containing oxidases), COX, and
mitochondria. The most dominant initial effect of increased ROS
production by endothelium appears to be the
attenuating action of O2·- on NO
signaling. Enhancement of this interaction seems to occur in multiple
vascular diseases107 as a result of increased
O2·- production through different
systems, including xanthine oxidase, NAD(P)H oxidase, and NOS. Because
peroxides have been observed to stimulate NOS activity by elevating
endothelial cell calcium69 70 and NOS
expression,104 as the production of oxidants
and NO increases in the endothelium or other
compartments in the normal or diseased vessel wall, ONOO-
formation is likely to occur and have a major signaling role. In the
absence of adequate levels of NO, the
pathophysiological effects of ROS are likely to
dominate the signaling and oxidative stress responses that are
observed.
The alterations in endothelial NO signaling caused by increased O2·- production contribute to important processes, such as the promotion of vasoconstriction or vasospasm, attenuation of the inhibition of platelet aggregation, and promotion of neutrophil adhesion. Elevated levels of NO will generally reverse these actions of O2·-. Although increases in NO also potentially influence regulatory systems in the vessel wall through the formation of RNS, the modulation of thiol redox, the generation of NO donors, and the inhibition of tissue catalase activity and mitochondrial function,9 the role of these NO-elicited processes in pathophysiological situations is not well understood. The effects of a simultaneous elevation of NO and O2·- will probably be dominated by the actions of ONOO-, which will change as tissue antioxidant systems such as GSH become stressed and antioxidant enzymes become inactivated. Because exposure of coronary arteries to hypoxia/reoxygenation results in an ONOO--mediated inactivation of PGI2 synthase and increased formation of unmetabolized PGH2,108 this may be one of the most prominent pathophysiological signal–like effects of ONOO- in vascular diseases.
Pathophysiological Consequences of Alterations
in Endothelial–Vascular Oxidant NO Signaling
One of the first pathophysiological conditions
observed to activate the production of increased levels
of endothelium-derived ROS and ROS-mediated signaling
responses was ischemia/reperfusion.65 In general,
ischemia/reperfusion appears to cause an acute increase in the
production of ROS and RNS by endothelium,
associated with an attenuation of NO signaling and activation of an
inflammatory response that often promotes a progression of the tissue
injury caused by ischemia. Interestingly, the signaling and
oxidant-scavenging activities of increased levels of NO appear to
attenuate many aspects of acute injury and the subsequent inflammatory
response caused by ischemia/reperfusion.
ROS and RNS appear to have prominent roles in many of the chronically activated signaling processes associated with the evolution of key vascular diseases, including diabetes, hypertension, and atherosclerosis.107 109 Studies in hypertensive humans and animal models have provided much evidence for the occurrence of a change in the balance between NO and O2·- signaling mechanisms toward an enhancement of oxidant-mediated processes.109 Alteration in the renin-angiotensin system resulting in an increased production of angiotensin II appears to be a primary mechanism in the evolution of the redox changes and development of disease processes.109 Increases in the activity and expression of NAD(P)H oxidase in the vessel wall by angiotensin II appear to be key participants in the impairment of endothelial NO function in animal hypertensive models.110 A polymorphism in the p22phox subunit of this oxidase has been observed to have a higher frequency of occurrence in humans with atherosclerotic coronary artery disease.111 Interestingly, although the pulmonary circulation is exposed to the elevated levels of angiotensin II during the development of systemic hypertension, this circulation does not exhibit hypertensive changes. A selective angiotensin II–induced increase in expression of endothelial NOS activity has been suggested as an explanation for the observed protection of the pulmonary circulation.112 In hypertension, atherosclerosis, and the vascular complications of diabetes, it appears that chronic exposure to oxidative or nitrosative stress promotes adaptations in signaling and in antioxidant defense systems and remodeling of the vessel wall in a manner that results in the appearance of relatively normal vascular function. However, under more severe conditions, the responses observed are likely to be dominated by the pathological actions of oxidant stress and RNS, such as a loss of the protective effects of PGs and NO as a result of an alteration in the metabolites that are produced, and the activation of inflammatory responses and thrombosis.
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Concluding Remarks |
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TopAbstractIntroductionOxidant Species and Their...What Controls the Production...Relationships Between Cellular...Vascular Processes Regulated by...Concluding RemarksReferences |
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Oxidant signaling mechanisms are now being recognized for their extremely important role in the control of vascular physiological and pathophysiological function. A large number of rather poorly understood signaling mechanisms seem to exist, and they appear to be controlled by the levels of each of the species present, by the tissue compartment in which the ROS are being formed, and by the degree of influence the species have on antioxidant defense mechanisms and key cellular redox systems. Most dietary antioxidants appear to have only modest physiological effects because they seem to protect against the consequences of "·OH" and ONOO- generation, such as lipid peroxidation, whereas the cellular concentrations of these antioxidants are likely to have only minimal effects on signaling mediated by O2·-, H2O2, NO, and thiol redox processes. Pharmacological agents that modulate the levels of specific reactive intermediates or that modulate enzymes involved in oxidant signaling pathways may have greater potential for therapeutic effects. Although a fine-tuned balance between the activation and adaptation of multiple mechanisms controlled by oxidative or nitrosative signaling probably occurs in most chronic vascular diseases, these adapted systems are more likely to respond in an abnormal manner under stressful conditions.
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Acknowledgments |
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I wish to thank members of our laboratory and collaborators cited in the references for their critical contributions to understanding or helping establish the significance of signaling mechanisms described in our previous publications. Studies from our laboratory have been funded by grants from the American Heart Association, the American Lung Association, and the National Institutes of Health (HL-31069 and HL-43023).
Received January 12, 2000; accepted March 17, 2000.
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References |
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TopAbstractIntroductionOxidant Species and Their...What Controls the Production...Relationships Between Cellular...Vascular Processes Regulated by...Concluding RemarksReferences |
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- Wolin MS. Reactive oxygen species and vascular signal transduction mechanisms. Microcirculation. 1996;3:1–17.[Medline] [Order article via Infotrieve]
- Fridovich I. Superoxide dismutase, regularities and irregularities. Harvey Lect. 1985;79:51–75.
-
Mugge A, Elwell JH, Peterson TE, Harrison DG.
Release of intact endothelium-derived relaxing factor
depends on endothelial superoxide dismutase activity.
Am J Physiol. 1991;260:C219–C225.
[Abstract/Free Full Text] -
Omar HA, Cherry PD, Mortelliti MP, Burke-Wolin T,
Wolin MS. Inhibition of coronary artery superoxide dismutase
attenuates endothelium-dependent and independent
nitrovasodilator relaxation. Circ Res. 1991;69:601–608.
[Abstract/Free Full Text] -
Cherry PD, Omar HA, Farrell KA, Stuart JS, Wolin MS.
Superoxide anion inhibits cGMP-associated bovine pulmonary
arterial relaxation. Am J Physiol. 1990;259:H1056–H1062.
[Abstract/Free Full Text] -
Abrahamsson T, Brandt U, Marklund SL, Sjoqvist P-O.
Vascular bound recombinant extracellular superoxide dismutase type C
protects against the detrimental effects of superoxide radicals on
endothelium-dependent relaxation. Circ Res. 1992;70:264–271.
[Abstract/Free Full Text] - Wink DA, Mitchell JB. Chemical biology of nitric oxide: insights into regulatory cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med. 1998;25:434–456.[Medline] [Order article via Infotrieve]
-
Davidson CA, Kaminski PM, Wolin MS. Nitric oxide
elicits prolonged relaxation of bovine pulmonary arteries via
endogenous peroxynitrite generation. Am J
Physiol. 1997;273:L437–L444.
[Abstract/Free Full Text] - Wolin MS, Davidson CA, Kaminski PM, Fayngersh RP, Mohazzab-H KM. Oxidant-nitric oxide signalling mechanisms in vascular tissue. Biochemistry (Mosc). 1998;63:810–816.[Medline] [Order article via Infotrieve]
- Gardner PR, Nguyen DH, White CW. Aconitase is a sensitive and critical target of oxygen poisoni