A computational model for analysis of SOD isoforms impact on nitric oxide biotransport in an arteriole

Abstract Background Atherosclerotic plaques can elaborate reactive oxygen species (ROS) that reduce nitric oxide (NO) bioavailability. Cellular detoxification enzymes including various peroxiredoxin (PRDX) and superoxide dismutase (SOD) isoforms can inactivate ROS. The omega-3 fatty acid (n3-FA) eicosapentaenoic acid (EPA) reduced cardiovascular (CV) events in high-risk patients (REDUCE-IT), a benefit not observed with mixed n3-FAs containing docosahexaenoic acid (DHA). Purpose The purpose of this study was to compare the effects of EPA and DHA on NO bioavailability and expression of detoxification enzymes in the vascular endothelium in vitro. Methods Human umbilical vein endothelial cells (HUVECs) were pretreated with EPA or DHA at equimolar levels (10 μM) for 2 h, then challenged with IL-6 at 12 ng/ml for 24 h. Proteomic analysis was performed using LC/MS to measure relative protein expression. Only significant (p<0.05) changes between treatment groups >1-fold were analyzed. Cells were stimulated with calcium ionophore to measure NO and peroxynitrite (ONOO-) release using a porphyrinic nanosensor. Results EPA, but not DHA, augmented PRDX-2 and SOD1 expression in HUVECs relative to IL-6 alone (1.2-fold and 1.6-fold, respectively, p=0.03). EPA also significantly lowered other isoforms unlike DHA. Either EPA or DHA increased thioredoxin expression by 1.5-fold (p=0.001) and 1.3-fold (p=0.02), respectively and decreased SOD2 expression by 1.5-fold (p=8.75E-11) and 1.6-fold (p=6.03E-9), respectively. IL-6 alone only increased expression of 6 detoxification enzymes by at least 1.2-fold, relative to vehicle. Unlike DHA, EPA also increased the NO to ONOO- release ratio by 36% (p<0.05) relative to IL-6 alone, without changes in NO synthase (eNOS) expression. Conclusions n3-FAs differentially influenced NO bioavailability and expression of ROS detoxification proteins, including peroxiredoxin and SOD isoforms. The net benefits of EPA on eNOS function and ROS detoxification may contribute to reduced atherothrombotic risk compared to DHA. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amarin Pharma Inc., Elucida Research

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Computational Model of Tyrosine Nitration Resulting from Oxidative Stress and Nitric Oxide Interaction in the Microcirculation

The FASEB Journal ◽

10.1096/fasebj.20.4.a726-c ◽

2006 ◽

Vol 20 (4) ◽

Author(s):

Mahendra Kavdia

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Computational Model ◽

Tyrosine Nitration

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A computational model for nitric oxide, nitrite and nitrate biotransport in the microcirculation: Effect of reduced nitric oxide consumption by red blood cells and blood velocity

Microvascular Research ◽

10.1016/j.mvr.2010.09.004 ◽

2010 ◽

Vol 80 (3) ◽

pp. 464-476 ◽

Cited By ~ 10

Author(s):

Prabhakar Deonikar ◽

Mahendra Kavdia

Keyword(s):

Nitric Oxide ◽

Computational Model ◽

Red Blood Cells ◽

Blood Cells ◽

Blood Velocity

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A Computational Model of Nitric Oxide Production and Transport in a Parallel Plate Flow Chamber

Annals of Biomedical Engineering ◽

10.1007/s10439-009-9658-5 ◽

2009 ◽

Vol 37 (5) ◽

pp. 943-954 ◽

Cited By ~ 16

Author(s):

A. A. Fadel ◽

K. A. Barbee ◽

D. Jaron

Keyword(s):

Nitric Oxide ◽

Computational Model ◽

Parallel Plate ◽

Flow Chamber ◽

Nitric Oxide Production ◽

Parallel Plate Flow Chamber ◽

Oxide Production

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Sex-specific computational models of the spontaneously hypertensive rat kidneys: factors affecting nitric oxide bioavailability

AJP Renal Physiology ◽

10.1152/ajprenal.00482.2016 ◽

2017 ◽

Vol 313 (2) ◽

pp. F174-F183 ◽

Cited By ~ 11

Author(s):

Ying Chen ◽

Jennifer C. Sullivan ◽

Aurélie Edwards ◽

Anita T. Layton

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Sex Differences ◽

Computational Model ◽

Solute Transport ◽

Spontaneously Hypertensive Rat ◽

Male And Female ◽

Spontaneously Hypertensive ◽

Hypertensive Rat ◽

And Oxidative Stress

The goals of this study were to 1) develop a computational model of solute transport and oxygenation in the kidney of the female spontaneously hypertensive rat (SHR), and 2) apply that model to investigate sex differences in nitric oxide (NO) levels in SHR and their effects on medullary oxygenation and oxidative stress. To accomplish these goals, we first measured NO synthase (NOS) 1 and NOS3 protein expression levels in total renal microvessels of male and female SHR. We found that the expression of both NOS1 and NOS3 is higher in the renal vasculature of females compared with males. To predict the implications of that finding on medullary oxygenation and oxidative stress levels, we developed a detailed computational model of the female SHR kidney. The model was based on a published male kidney model and represents solute transport and the biochemical reactions among O2, NO, and superoxide ([Formula: see text]) in the renal medulla. Model simulations conducted using both male and female SHR kidney models predicted significant radial gradients in interstitial fluid oxygen tension (Po2) and NO and [Formula: see text] concentration in the outer medulla and upper inner medulla. The models also predicted that increases in endothelial NO-generating capacity, even when limited to specific vascular segments, may substantially raise medullary NO and Po2 levels. Other potential sex differences in SHR, including [Formula: see text] production rate, are predicted to significantly impact oxidative stress levels, but effects on NO concentration and Po2 are limited.

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Localization of endothelial nitric oxide synthase in the normal and failing human atrial myocardium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100166397 ◽

1996 ◽

Vol 54 ◽

pp. 786-787

Author(s):

Chi-Ming Wei ◽

Margarita Bracamonte ◽

Shi-Wen Jiang ◽

Richard C. Daly ◽

Christopher G.A. McGregor ◽

...

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Cardiac Tissues ◽

Mammalian Tissues ◽

End Stage Heart Failure ◽

End Stage ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Nitric oxide (NO) is a potent endothelium-derived relaxing factor which also may modulate cardiomyocyte inotropism and growth via increasing cGMP. While endothelial nitric oxide synthase (eNOS) isoforms have been detected in non-human mammalian tissues, expression and localization of eNOS in the normal and failing human myocardium are poorly defined. Therefore, the present study was designed to investigate eNOS in human cardiac tissues in the presence and absence of congestive heart failure (CHF).Normal and failing atrial tissue were obtained from six cardiac donors and six end-stage heart failure patients undergoing primary cardiac transplantation. ENOS protein expression and localization was investigated utilizing Western blot analysis and immunohistochemical staining with the polyclonal rabbit antibody to eNOS (Transduction Laboratories, Lexington, Kentucky).

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