NAD(P)H Oxidase Inhibition Improves Endothelial Function in Rat and Human Blood Vessels

Hamilton, Carlene A.; Brosnan, M J; Al-Benna, Sammy; Berg, G; Dominiczak, Anna F.

doi:10.1161/01.hyp.0000037063.90643.0b

Cited by 157 publications

(130 citation statements)

References 36 publications

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“…Recently, apocynin was proposed as an antioxidant in cultured endothelial and vascular smooth muscle cells but not as an inhibitor of NOX (25). Earlier reports, however, verified that apocynin decreases NADPH-stimulated O 2 Ϫ generation in the vasculature (9,18,20,22,28,32,54), where apocynin may be activated by peroxidases in vascular cells instead of MPOs (55,56). Since there are abundant cell types in blood and in vascular wall, including granulocyte, MPOs may be present in the vessel wall (56).…”

Section: Discussionmentioning

confidence: 99%

“…After 20 min of constant flow (2 ml/s) in either the forward or reverse direction, the respective vessel segments were immediately frozen in liquid nitrogen and stored in Ϫ80°C until Western blot analysis measurement. The artery segments were homogenized in a lysis buffer containing 50 mmol/l ␤-glycerophosphate, 100 mol/l sodium orthovanadate, 2 mmol/l magnesium chloride, 1 mmol/l EGTA, 0.5% Triton X-100, 1 mmol/l DL-dithiothreitol, 20 mol/l pepstatin, 20 mol/l leupeptin, 0.1 U/ml aprotinin, and 1 mmol/l phenylmethylsulfonyl fluoride and then incubated on ice for 1 h. The sample was centrifuged at 1,000 g for 15 min at 1°C, and the supernatant was collected. The total protein was measured by a BCA kit (Bio-Rad).…”

Section: Animal Preparation and Vessel Harvestmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Animal Preparation and Vessel Harvestmentioning

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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“…The formation of O 2 −• by the endothelial NADPH oxidase accounts for the reduced NO bioavailability, development of endothelial dysfunction from the aortic ring of gp91phox-knockout mice (gp91phox−/−) [50]. In this context, apocynin (4-hydroxy-3-methoxyacetophenonone) has been demonstrate to act as a potent and selective inhibitor of NADPH oxidase system in both in vitro and animal models [51][52][53] by interfering with the translocation of an essential cytosolic protein, p47phox [54][55][56]. Diphenylene iodonium (DPI) nonspecifically inhibits flavoprotein-containing enzymes, including NADPH oxidases, NOS, and complex I of mitochondrial electron transport chain [57].…”

Section: Discussionmentioning

confidence: 99%

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

Rouhanizadeh

Hwang

Clempus

et al. 2005

Free Radical Biology and Medicine

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Modified low-density lipoprotein (LDL) induces reactive oxygen species (ROS) production by vascular cells. It is unknown if specific oxidized components in these LDL particles such as oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (ox-PAPC) can stimulate ROS production. Bovine aortic endothelial cells (BAEC) were incubated with ox-PAPC (50 μg/ml). At 4 h, ox-PAPC significantly enhanced the rate of O 2 −• production. Pretreatment of BAEC in glucose-free Dulbecco's modified Eagle's medium plus 10 mM 2-deoxyglucose (2-DOG), the latter being an antimetabolite that blocks NADPH production by the pentose shunt, significantly reduced the rate of O 2 −• production. The intensity of NAD(P)H autofluorescence decreased by 28 ± 12% in BAEC incubated with ox-PAPC compared to untreated cells, with a further decrease in the presence of 2-DOG. Ox-PAPC also increased Nox4 mRNA expression by 2.4-fold ± 0.1 while pretreatment of BAEC with the small interfering RNA (siNox4) attenuated Nox4 RNA expression. Ox-PAPC further reduced the level of glutathione while pretreatment with apocynin (100 μM) restored the GSH level (control = 22.54 ± 0.23, GSH = 18.06 ± 0.98, apocynin = 22.55 ± 0.60,.17 ± 0.36 nmol/10 6 cells). Treatment with ox-PAPC also increased MMP-2 mRNA expression accompanied by a 1.5-fold increase in MMP-2 activity. Ox-PAPC induced vascular endothelial O 2 −• production that appears to be mediated largely by NADPH oxidase activity.

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“…7,8 Angiotensin II is well known to induce NADPH oxidase, which in turn has a crucial role in the pathogenesis of vascular dysfunction. [9][10][11] Using SHR-SP, olmesartan, a high-affinity ARB and valsartan, a low-affinity ARB, were compared in terms of protection against vascular dysfunction, at doses that showed the same hypotensive effects.…”

Section: Introductionmentioning

confidence: 99%

Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats

Jin

Ikeda²,

Saito³

et al. 2009

Hypertens Res

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Angiotensin II receptor blockers (ARBs) vary in their binding affinities to angiotensin II type 1 (AT 1 ) receptors in in vitro experiments. We compared a high-affinity ARB, olmesartan, and a low-affinity ARB, valsartan, in terms of their vascular protective effects in stroke-prone spontaneously hypertensive rats (SHR-SP). Blood pressure was equally reduced by placebo, olmesartan (1 mg kg À1 ) and valsartan (3 mg kg À1 ) daily for 2 weeks. In another experiment, 12-week-old SHR-SP were fed 8% salt, and olmesartan (1 mg kg À1 ), valsartan (3 mg kg À1 ) or placebo were administered daily until a survival rate of 60% was reached. In the experiment using SHR-SP, the reduction of acetylcholine-induced vascular relaxation and the increase of p22 phox expression in the placebo-treated group were significantly attenuated by olmesartan and valsartan, but this attenuation was significantly greater for olmesartan. In immunohistological analysis, all areas positive for angiotensin II, p22 phox and 4-hydroxy-2-nonenal were significantly reduced by olmesartan and valsartan, but again this reduction was significantly greater for olmesartan. In salt-loaded SHR-SP, the number of days to reach a 60% survival rate was 25 and 42 in placebo and valsartantreated rats, respectively, and this represented a significant difference. The survival rate in olmesartan-treated rats was 95% at day 42, when valsartan-treated rats reached 60% survival, and this difference was also significant. In the surviving rats, olmesartan, but not valsartan, augmented acetylcholine-induced vascular relaxation and attenuated vascular p22 phox expression. Thus, heterogeneity in binding affinity to AT 1 receptors among ARBs may result in different degrees of vascular protection and lifespan extension.

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NAD(P)H Oxidase Inhibition Improves Endothelial Function in Rat and Human Blood Vessels

Cited by 157 publications

References 36 publications

NADPH oxidase has a directional response to shear stress

NADPH oxidase has a directional response to shear stress

Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase

Significance of angiotensin II receptor blockers with high affinity to angiotensin II type 1 receptors for vascular protection in rats

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