NAD(P)H oxidase-derived peroxide mediates elevated basal and impaired flow-induced NO production in SHR mesenteric arteries in vivo

Zhou, Xiaosun; Bohlen, H. G.; Miller, Steven J.; Unthank, Joseph L.

doi:10.1152/ajpheart.00114.2008

Cited by 50 publications

(100 citation statements)

References 78 publications

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“…This increased contractility observed in HF arteries, not in NF vessels, might oppose diameter expansion in 12-mo-old male rats. This is in agreement with a previous study (48) showing a rise in NO production in HF arteries, which was opposed by O 2 Ϫ produced by NAD(P)H oxidase in spontaneously hypertensive rats. This is also in agreement with our previous study showing in 2-yr-old male rats that hydralazine, without affecting systemic blood pressure (20), restored flow-mediated diameter enlargement in rat mesenteric arteries (15).…”

Section: Discussionsupporting

confidence: 94%

Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries

Tarhouni

Freidja

Guihot³

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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tance arteries, a chronic increase in blood flow induces hypertrophic outward remodeling. This flow-mediated remodeling (FMR) is absent in male rats aged 10 mo and more. As FMR depends on estrogens in 3-mo-old female rats, we hypothesized that it might be preserved in 12-mo-old female rats. Blood flow was increased in vivo in mesenteric resistance arteries after ligation of the side arteries in 3-and 12-mo-old male and female rats. After 2 wk, high-flow (HF) and normal-flow (NF) arteries were isolated for in vitro analysis. Arterial diameter and cross-sectional area increased in HF arteries compared with NF arteries in 3-mo-old male and female rats. In 12-mo-old rats, diameter increased only in female rats. Endothelial nitric oxide synthase expression and endothelium-mediated relaxation were higher in HF arteries than in NF arteries in all groups. ERK1/2 phosphorylation, NADPH oxidase subunit expression levels, and arterial contractility to KCl and to phenylephrine were greater in HF vessels than in NF vessels in 12-mo-old male rats only. Ovariectomy in 12-mo-old female rats induced a similar pattern with an increased contractility without diameter increase in HF arteries. Treatment of 12-mo-old male rats and ovariectomized female rats with hydralazine, the antioxidant tempol, or the angiotensin II type 1 receptor blocker candesartan restored HF remodeling and normalized arterial contractility in HF vessels. Thus, we found that FMR of resistance arteries remains efficient in 12-mo-old female rats compared with age-matched male rats. A balance between estrogens and vascular contractility might preserve FMR in mature female rats. microcirculation; remodeling; blood flow; shear stress; sex; aging; estrogen RESISTANCE ARTERIES control local blood flow to organs. They are able to adapt in response to changes in hemodynamic conditions, even in the adult. A chronic increase in blood flow (shear stress) in these vessels induces outward hypertrophic remodeling associated with increased endothelium [nitric oxide (NO)]-dependent dilation, as shown in male (2,5, 33) and female rats (37). Chronic increases in blood flow occur in physiological conditions such as growth, chronic exercise, or pregnancy as well as in ischemic disorders, where they contribute to collateral arteries growth (7, 36). Flowmediated outward remodeling of resistance arteries involves a transient inflammatory response (1) and oxidative stress (2) that favors the formation of peroxinitrite, which then activates metalloproteinases and extracellular matrix digestion (2,8,14,16,19). The final step, leading to diameter enlargement, requires a dilator stimulus (17). Flow-mediated outward remodeling is also associated with a compensatory increase in wall mass (11, 32) due to ANG II type 1 receptor activation of ERK1/2 (11).As shown in male rats, flow-mediated remodeling of mesenteric resistance arteries does not occur in male rats aged 12 mo (40) or 24 mo (15). Although no diameter enlargement occurred in arteries after increasing blood flow, endotheliummedia...

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Section: Discussionsupporting

confidence: 94%

Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries

Tarhouni

Freidja

Guihot³

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…The gp91ds-tat is a peptide inhibitor that interferes with the binding of gp91 phox with gp47 phox to inactivate NOX (42,47). Zhou et al (58) recently applied gp91ds-tat to block NOX in the mesenteric artery of rats. In the present study, gp91ds-tat inhibited NOX during the stimulation of shear stress, which verifies the role of NOX.…”

Section: Discussionmentioning

confidence: 99%

NADPH oxidase has a directional response to shear stress

Godbole¹,

Lu²,

Guo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Godbole AS, Lu X, Guo X, Kassab GS. NADPH oxidase has a directional response to shear stress. Am J Physiol Heart Circ Physiol 296: H152-H158, 2009. First published November 14, 2008 doi:10.1152/ajpheart.01251.2007.-Vessel regions with predilection to atherosclerosis have negative wall shear stress due to flow reversal. The flow reversal causes the production of superoxides (O 2 Ϫ ), which scavenge nitric oxide (NO), leading to a decrease in NO bioavailability and endothelial dysfunction. Here, we implicate NADPH oxidase as the primary source of O 2 Ϫ during full flow reversal. Nitrite production and the degree of vasodilation were measured in 46 porcine common femoral arteries in an ex vivo system. Nitrite production and vasodilation were determined before and after the inhibition of NADPH oxidase, xanthine oxidase, or mitochondrial oxidase. NADPH oxidase inhibition with gp91ds-tat or apocynin restored nitrite production and vasodilation during reverse flow. Xanthine oxidase inhibition increased nitrite production at the highest flow rate, whereas mitochondrial oxidase inhibition had no effect. These findings suggest that the NADPH oxidase system can respond to directional changes of flow and is activated to generate O 2 Ϫ during reverse flow in a dose-dependent fashion. These findings have important clinical implications for oxidative balance and NO bioavailability in regions of flow reversal in a normal and compromised cardiovascular system. superoxide; nitric oxide; oxidative balance; reduced nicotinamide adenine dinucleotide phosphate NITRIC OXIDE (NO) is released by endothelial cells to regulate blood vessel diameter acutely as well as to maintain long-term homeostatic conditions of the vessel wall (4,30). NO is produced in the endothelium from L-arginine by the enzyme endothelial NO synthase (eNOS) (4, 41) and is released in response to endothelial shear stress and other stimuli such as acetylcholine (4). Wall shear stress (WSS) has also been found to regulate the activity and expression of eNOS (34,40).Oscillatory and reverse WSS have negative effects on the endothelium due to superoxide (O 2 Ϫ ) production (14, 27, 28, 36, 52). It has been found that reverse flow in blood vessels causes reduced NO due to increased O 2 Ϫ production (36). Since NO is atheroprotective, regions of oscillatory and reverse WSS are more prone to atherosclerosis. Regions near branch points and curved vessels produce near-wall reverse flow (15,16).O 2 Ϫ can quickly inactivate NO, causing reduced NO bioavailability and endothelial dysfunction (9, 33). This endothelial dysfunction is implicated in atherosclerosis, hypertension, and heart failure (9,13,14,18,21). Reduced NO in the vessel wall impairs endothelium-dependent vasodilation, decreases inhibition of platelet and leukocyte adhesion, and is linked to the development of intimal hyperplasia (4, 21, 51). Our group has previously shown that NO production is reduced during reverse flow and that the addition of Tempol (an O 2 Ϫ scavenger) restored NO production in reverse flow to...

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“…The peptide contains a nine-amino-acid sequence of the NOX2 intracellular B-loop that binds the NOX organizer protein p47 phox , thereby preventing assembly of the active NOX2 complex (74,99,133,145,194,195) (Fig. 2).…”

Section: Nox2ds-tatmentioning

confidence: 99%

“…Although the tat peptide was shown to localize to the cytoplasm of neutrophils (35), NOX2ds-tat inhibited superoxide formation released by intact neutrophils only by 35%; while it inhibited 80% of superoxide generated in cell-free assays (145) with an IC 50 of 0.74 lM (36). Still, NOX2ds-tat was shown to be effective in several in vivo animal models, either applied intravenously or expressed via adenoviral infection, indicating that it reaches its destination (74,99,133,194,195). To rule out effects caused by the tat peptide itself (25), scrambled nine-amino-acid peptide sequences linked to the tat peptide were used as controls in most of the studies (74,133,145,194).…”

Section: Nox2ds-tatmentioning

confidence: 99%

“…Remarkably, the use of NOX2 KO animals and studies using NOX2ds-tat (98,99,194) suggest that NOX2 is not involved in blood pressure regulation or hypertension in mice. In contrast, a role of NOX2 in hypertension in spontaneously hypertensive rats (SHRs) based on NOX2 inhibition by NOX2ds-tat was suggested (158,195). Thus, NOX2-derived ROS might be involved in baroreceptor reflex regulation in these rats (158).…”

Section: Fig 7 Nox Enzymes As Validated Therapeutic Targetsmentioning

confidence: 99%

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Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Altenhöfer

Radermacher

Kleikers

et al. 2015

Antioxidants & Redox Signaling

439

417

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Significance: Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Recent Advances: Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms. Critical Issues: Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease. Future Directions: The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition. Antioxid. Redox Signal. 23, 406-427.

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NAD(P)H oxidase-derived peroxide mediates elevated basal and impaired flow-induced NO production in SHR mesenteric arteries in vivo

Cited by 50 publications

References 78 publications

Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries

Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries

NADPH oxidase has a directional response to shear stress

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

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