Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

Lee, Doug Yoon; Wauquier, Fabien; Eid, Assaad A.; Roman, Linda J.; Ghosh-Choudhury, Goutam; Khazim, Khaled; Block, Karen; Gorin, Yves

doi:10.1074/jbc.m113.470971

Cited by 116 publications

(117 citation statements)

References 78 publications

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“…Mitochondrial oxidative stress is a key mechanism in the onset and propagation of cardiovascular diseases as loss of MnSOD results in dilated cardiomyopathy and limits the survival of mice to 2 weeks (5). Increased mitochondrial oxidative stress also occurs due to an activated renin-angiotensin system that impacts heart and the vascular system, and it has also been implicated in hypertension (41,42). This study shows a redox regulatory mechanism in MKK4 activation resulting in MnSOD activation in ECs.…”

Section: Discussionmentioning

confidence: 64%

Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells

Kundumani‐Sridharan

Das

2015

Journal of Biological Chemistry

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Background:The mechanism underlying thioredoxin-induced expression of manganese superoxide dismutase (MnSOD) is unknown. Results: Reduced thioredoxin activates the MKK4-NFB pathway to repress MKK7-AP-1-mediated inhibition of MnSOD expression. Conclusion: Cellular redox status regulates gene expression via redox control of MKK4, an MAPK. Significance: This study reveals a novel mechanism underlying transcriptional regulation of MnSOD encoding a critical antioxidant enzyme.

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Section: Discussionmentioning

confidence: 64%

Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells

Kundumani‐Sridharan

Das

2015

Journal of Biological Chemistry

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“…First, increased generation of metabolic intermediates may be toxic. Succinate, a ligand of the G protein-coupled receptor GPR91, can activate the renin-angiotensin system (39)(40)(41), and the activation of angiotensin II may result in NADPH oxidase 4-generated (Nox4-generated) mitochondrial oxidative damage (42,43), leading to a feed-forward mechanism that promotes kidney injury in diabetes. Fumarate, which also accumulates in the diabetic kidney and urine of a type 1 model of DKD, is a potent inducer of HIF-1α and TGF-β, both of which could contribute to kidney disease pathology (44).…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Sas¹,

Kayampilly²,

Byun³

et al. 2016

JCI Insight

216

218

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“…For example, Ang II can induce eNOS uncoupling and thereby reduce NO bioavailability and increase oxidative stress. 67,68 Moreover, we recently found that renal Ang II content is augmented, and renal CAT1 expression is reduced in diet-induced obese hypertensive mice. 5 To determine whether augmented Ang II levels can reduce renal l-arginine transport, we examined the effects of exogenous Ang II on 3 H-l-arginine transport in renal and endothelial cells.…”

Section: Mechanistic Insights Activation Of the Raas As A Mediator Ofmentioning

confidence: 99%

“…Por ejemplo, la Ang II puede inducir el desacople de la eNOS y, por lo tanto, disminuir la biodisponibilidad de NO y aumentar el estrés oxidativo. 67,68 Además, recientemente hallamos que en ratones hipertensos obesos con dieta inducida el contenido de la Ang II en el riñón aumenta y la expresión del CAT1 renal se reduce.…”

Section: Perspectivas Mecanicistasunclassified

Say NO to Obesity-Related Hypertension

2016

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O besity and its complications represent one of the major emerging challenges for the developed world. 1,2 Hypertension is a common sequelae of obesity, 3,4 and the obesity pandemic is estimated to contribute to 75% of cases of hypertension in men and 65% in women.1 Frequently, subjects with obesity are resistant to standard antihypertensive medication, 4 and poor understanding of the precise mechanisms underlying the link between obesity and hypertension has presented roadblocks for the development of new and effective therapy. 4 In this context, we recently found that obesity is associated with reduced nitric oxide (NO) bioavailability caused by impaired transport of its substrate l-arginine and that augmentation of endothelial l-arginine transport prevents experimental obesity-induced hypertension.5 Findings by others also provide clear evidence that endothelial dysfunction plays an important role in the pathogenesis of hypertension 6,7 including that associated with obesity. 8In the current review, we will discuss the role of the l-arginine-NO pathway in the long-term regulation of blood pressure, its complex inter-relationship with other key neurohormonal and biochemical determinants of arterial pressure, and the way in which this system becomes deranged in obesity-related hypertension. l-Arginine-NO PathwayNO is well recognized as a pivotal endogenous modulator of vascular tone and endothelial function.9 l-Arginine is the sole substrate for NO formation and transport of extracellular l-arginine via cationic amino acid transporter-1 (CAT1) is a rate limiting factor for endothelial NO synthase (eNOS)-dependent NO formation (Figure 1). [9][10][11] This occurs despite the fact that intracellular concentration of l-arginine far exceeds the Michaelis constant K m of eNOS for l-arginine, and this phenomenon is commonly referred to as the l-arginine paradox. 9 The precise factors underlying this paradox remain to be determined, but some of the proposed mechanisms include sequestration of intracellular l-arginine into pools that are not accessible to membrane-bound eNOS, the presence of endogenous eNOS inhibitors such as asymmetrical dimethylarginine and colocalization of CAT1, and eNOS within the plasma membrane of endothelial cells, which facilitates the use of extracellular l-arginine for eNOS-dependent NO formation.9-11 Regardless of the mechanism(s) involved, the presence of the l-arginine paradox creates a crucial role for l-arginine transporters in regulating NO bioavailability and consequently endothelial function. Does Endothelial Dysfunction Precede Hypertension in the Setting of Obesity?Although there is a plethora of data to support an association between endothelial dysfunction and hypertension, [12][13][14] the precise relationship between these 2 phenomena remains complex and undefined. Weisbrod et al 15 recently demonstrated that endothelial function as measured by aortic relaxation to acetylcholine ex vivo was impaired within 2 months of placing mice on a high fat, high sucrose diet. Howeve...

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Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

Cited by 116 publications

References 78 publications

Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells

Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells

Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Say NO to Obesity-Related Hypertension

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