Modeling the influence of superoxide dismutase on superoxide and nitric oxide interactions, including reversible inhibition of oxygen consumption

Buerk, Donald G.; Lamkin-Kennard, Kathleen A.; Jaron, Dov

doi:10.1016/s0891-5849(03)00178-3

Cited by 72 publications

(71 citation statements)

References 48 publications

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“…This value is similar to the predictions of other NO transport models [8,20,35]. Note that these models used a high rate of NO production by the endothelium, estimated by fitting the data [36] for perivascular NO concentrations using a mathematical model [8] with the assumption that NOS3-derived NO from the endothelium was the sole source in the vasculature.…”

Section: Discussionsupporting

confidence: 81%

Vascular and perivascular nitric oxide release and transport: Biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)

Chen

Popel

2007

Free Radical Biology and Medicine

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Nitric oxide (NO) derived from nitric oxide synthase (NOS) is an important paracrine effector that maintains vascular tone. The release of NO mediated by NOS isozymes under various O 2 conditions critically determines the NO bioavailability in tissues. Because of experimental difficulties, there has been no direct information on how enzymatic NO production and distribution change around arterioles under various oxygen conditions. In this study, we used computational models based on the analysis of biochemical pathways of enzymatic NO synthesis and the availability of NOS isozymes to quantify the NO production by neuronal NOS (NOS1) and endothelial NOS (NOS3). We compared the catalytic activities of NOS1 and NOS3 and their sensitivities to the concentration of substrate O 2 . Based on the NO release rates predicted from kinetic models, the geometric distribution of NO sources and mass balance analysis, we predicted the NO concentration profiles around an arteriole under various O 2 conditions. The results indicated that NOS1-catalyzed NO production was significantly more sensitive to ambient O 2 concentration than that catalyzed by NOS3. Also, the high sensitivity of NOS1 catalytic activity to O 2 was associated with significantly reduced NO production and therefore NO concentrations, upon hypoxia. Moreover, the major source determining the distribution of NO was NOS1, which was abundantly expressed in the nerve fibers and mast cells close to arterioles, rather than NOS3, which was expressed in the endothelium. Finally, the perivascular NO concentration predicted by the models under conditions of normoxia was paradoxically at least an order of magnitude lower than a number of experimental measurements, suggesting a higher abundance of NOS1 or NOS3 and/or the existence of other enzymatic or nonenzymatic sources of NO in the microvasculature.

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Section: Discussionsupporting

confidence: 81%

Vascular and perivascular nitric oxide release and transport: Biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)

Chen

Popel

2007

Free Radical Biology and Medicine

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“…Our results suggest that the SOD-induced [O 2 Ϫ ] cyt reduction raises [NO] cyt in preconstricted pericytes from 0.7 to 1.3 nM, which in turn raises the concentration of cGMP by 0.3 M, resulting in a lower fraction of phosphorylated MLC and leading to vasorelaxation, as shown in Fig. 7.…”

supporting

confidence: 51%

“…As a first step, we examined the dependence of model variables on cGMP levels. As described above, four variables are taken to vary directly in proportion to [ (Table 7), k 2 Myo is expected to be quite sensitive to physiological [cGMP] variations. In contrast, the open probability of K Ca channels attains its equilibrium value of 0.059 much faster, as soon as [cGMP] reaches 9 M. However, since P o KCa is so low, cGMP-induced (or NO-induced) variations in K Ca currents should remain small.…”

Section: Contribution Of Cgmp Pathways To Resting [Ca] Cytmentioning

confidence: 99%

Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta

Edwards

Cao

Pallone

2011

American Journal of Physiology-Renal Physiology

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signaling and MLC phosphorylation. At concentrations above 1 nM, O 2 Ϫ is predicted to modulate [Cacyt] and MCLP activity mostly by reducing NO bioavailability. The DVR vasoconstriction that is induced by high concentrations of H 2O2 can be explained by H2O2-mediated downregulation of MLCP and SERCA activity. We conclude that intrinsic generation of NO by the DVR wall may be sufficient to inhibit vasoconstriction by maintaining suppression of MLC phosphorylation. calcium signaling; hydrogen peroxide; superoxide; vascular smooth muscle NITRIC OXIDE (NO) acts as a local vasodilator in the renal medulla and plays an important role in the maintenance of medullary perfusion, medullary oxygenation, and blood pressure. Chronic inhibition of nitric oxide synthase (NOS) reduces medullary blood flow (MBF) and is associated with sodium retention and the development of hypertension (8, 41). Whereas NO increases MBF by promoting the vasodilation of descending vasa recta (DVR) or juxtamedullary arterioles, superoxide (O 2 Ϫ ) and hydrogen peroxide (H 2 O 2 ) act to reduce MBF by mechanisms that remain to be fully elucidated (17,37). In addition, NO inhibits, whereas O 2 Ϫ enhances, thick ascending limb sodium reabsorption (23). Hence, interactions between NO and O 2 Ϫ likely contribute to the long-term control of blood pressure; when the balance between these two radicals is shifted in favor of O 2 Ϫ (such as in diabetes and atherosclerosis, conditions that promote oxidative stress), renal vasoconstriction and tubular reabsorption increase, favoring hypertension (17).In a recent microperfusion study of DVR (4), we showed that intrinsic production of NO and reactive oxygen species (ROS) affects DVR vasoactivity. To elucidate the cellular pathways by which NO, O 2 Ϫ , and H 2 O 2 modulate DVR contraction, in the present study we expanded our mathematical model of Ca 2ϩ signaling in DVR pericytes to account for the effects of NO and ROS and to predict the degree of vessel contraction.Smooth muscle contraction is initiated by an increase in cytosolic Ca 2ϩ concentration ([Ca] cyt ). Increased binding of Ca 2ϩ to calmodulin (CaM) activates myosin light chain kinase (MLCK), which then phosphorylates myosin light chains (MLC) in the presence of ATP, thereby increasing the cycling rate of actin-myosin cross-bridge formation and generating the active force needed for muscle contraction. Most of the vasodilatory effects of NO on smooth muscle cells appear to be mediated by cGMP. Activity of the NO/cGMP pathway favors reduction in the fraction of phosphorylated myosin, via two different mechanisms: 1) an increase in the activity of myosin light chain phosphatase (MLCP), and 2) modulation of Ca 2ϩ transport that lowers [Ca] cyt , decreases Ca 2ϩ binding to CaM, and thereby reduces MLCK activity.We incorporated these and other signaling pathways in our mathematical model of DVR pericytes as described in MODEL DESCRIPTION. The data on which this and prior versions of the model are based have been largely derived from studies of DVR peric...

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“…Instead, the limited diffusion properties of O 2 c -(2) dictate that the formation of peroxynitrite will predominantly occur in the vicinity of O 2 c -generation. Since the reaction between O 2 c -and NO directly competes with that of O 2 c -and SODs (20), the generation of peroxynitrite also depends on the availability of SODs. Thus, when SODs become inactivated, as occurs in NAFLD (138, 209) (section ''Proteins''), and iNOS is simultaneously induced, which takes place in NAFLD (122) as well as IR (82), the formation of peroxynitrite and derivative radicals (next paragraph) will increase.…”

Section: Reactive Nitrogen Speciesmentioning

confidence: 99%

Reactive Oxygen and Nitrogen Species in Steatotic Hepatocytes: A Molecular Perspective on the Pathophysiology of Ischemia-Reperfusion Injury in the Fatty Liver

Reiniers

Golen

Gulik

et al. 2014

Antioxidants & Redox Signaling

109

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Significance: Hepatic ischemia-reperfusion (IR) injury results from the temporary deprivation of hepatic blood supply and is a common side effect of major liver surgery (i.e., transplantation or resection). IR injury, which in most severe cases culminates in acute liver failure, is particularly pronounced in livers that are affected by nonalcoholic fatty liver disease (NAFLD). In NAFLD, fat-laden hepatocytes are damaged by chronic oxidative/ nitrosative stress (ONS), a state that is acutely exacerbated during IR, leading to extensive parenchymal damage. Recent Advances: NAFLD triggers ONS via increased (extra)mitochondrial fatty acid oxidation and activation of the unfolded protein response. ONS is associated with widespread protein and lipid (per)oxidation, which reduces the hepatic antioxidative capacity and shifts the intracellular redox status toward an oxidized state. Moreover, activation of the transcription factor peroxisome proliferator-activated receptor a induces expression of mitochondrial uncoupling protein 2, resulting in depletion of cellular energy (ATP) reserves. The reduction in intracellular antioxidants and ATP in fatty livers consequently gives rise to severe ONS and necrotic cell death during IR. Critical Issues: Despite the fact that ONS mediates both NAFLD and IR injury, the interplay between the two conditions has never been described in detail. An integrative overview of the pathophysiology of NAFLD that renders steatotic hepatocytes more vulnerable to IR injury is therefore presented in the context of ONS. Future Directions: Effective methods should be devised to alleviate ONS and the consequences thereof in NAFLD before surgery in order to improve resilience of fatty livers to IR injury.

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Modeling the influence of superoxide dismutase on superoxide and nitric oxide interactions, including reversible inhibition of oxygen consumption

Cited by 72 publications

References 48 publications

Vascular and perivascular nitric oxide release and transport: Biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)

Vascular and perivascular nitric oxide release and transport: Biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3)

Cellular mechanisms underlying nitric oxide-induced vasodilation of descending vasa recta

Reactive Oxygen and Nitrogen Species in Steatotic Hepatocytes: A Molecular Perspective on the Pathophysiology of Ischemia-Reperfusion Injury in the Fatty Liver

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