Apocynin-induced vasodilation involves Rho kinase inhibition but not NADPH oxidase inhibition

Schlüter, Torsten; Steinbach, Antje; Steffen, Anȷa; Rettig, Rainer; Grisk, Olaf

doi:10.1093/cvr/cvn185

Cited by 82 publications

(69 citation statements)

References 30 publications

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“…(8,39,45). Those signal pathways may be involved in a myogenic response of the blood vessel (38,49). In the present study, we observed that the vessels incubated with apocynin could not develop mygenic tone in physiological loading at zero flow and remained at a significantly larger diameter than in the control, which is consistent with previous observations (49).…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

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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“…30,31 It also inhibits Rho kinase, 32 a mechanism which may account for a large part of its vasodilator actions. 32 …”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the use of apocynin has potentially lead to an overestimation of the relevance of NADPH oxidases [32][33][34] and may need to be revisited or reinterpreted. Nevertheless, we included apocynin in our experiments to allow a direct comparison of its efficacy to that of VAS2870.…”

Section: Wky Nox1mentioning

confidence: 99%

Oxidative Stress and Endothelial Dysfunction in Aortas of Aged Spontaneously Hypertensive Rats by NOX1/2 Is Reversed by NADPH Oxidase Inhibition

et al. 2010

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Abstract-Arterial hypertension is associated with increased levels of reactive oxygen species, which may scavenge endothelium-derived NO and thereby diminish its vasorelaxant effects. However, the quantitatively relevant source of reactive oxygen species is unclear. Thus, this potential pathomechanism is not yet pharmacologically targetable. Several enzymatic sources of reactive oxygen species have been suggested: uncoupled endothelial NO synthase, xanthine oxidase, and NADPH oxidases. Here we show that increased reactive oxygen species formation in aortas of 12-to 14-month-old spontaneously hypertensive rats versus age-matched Wistar Kyoto rats is inhibited by the specific NADPH oxidase inhibitor VAS2870 but neither by the xanthine oxidase inhibitor oxypurinol nor the NO synthase inhibitor N G -nitro-L-arginine methyl ester. NADPH oxidase activity, as well as protein expression of its catalytic subunits, NOX1 and NOX2, was increased in the aortas of spontaneously hypertensive rats, whereas the expression of NOX4 protein, the most abundant NOX isoform, was not significantly changed. Impaired acetylcholine-induced relaxation of spontaneously hypertensive rat aortas was significantly improved by VAS2870. In conclusion, NOX1 and NOX2 but not NOX4 proteins are increased in aged spontaneously hypertensive rat aortas. Importantly, these NOX isoforms, in particular, ectopic expression of NOX1 in endothelial cells, appear to affect vascular function in an NADPH oxidase inhibitor-reversible manner. NADPH oxidases may, thus, be a novel target for the treatment of systemic hypertension. (Hypertension. 2010;56:490-497.)

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“…In spontaneously hypertensive rats, Rho kinase inhibition and apocynin treatment attenuated acetylcholine-stimulated contraction of common carotid arteries (10), while apocynin was implicated in Rho kinase inhibition in renal intralobar arteries (34). Additional studies are needed to identify a potential role for Rho kinase-mediated PA contraction in ventilated PPHN lambs and to determine the impact of intratracheal apocynin on Rho kinase activity in our model.…”

Section: Discussionmentioning

confidence: 99%

Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

Wedgwood

Lakshminrusimha

Farrow

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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RH. Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 302: L616 -L626, 2012. First published December 23, 2011 doi:10.1152/ajplung.00064.2011.-NADPH oxidase is a major source of superoxide anions in the pulmonary arteries (PA). We previously reported that intratracheal SOD improves oxygenation and restores endothelial nitric oxide (NO) synthase (eNOS) function in lambs with persistent pulmonary hypertension of the newborn (PPHN). In this study, we determined the effects of the NADPH oxidase inhibitor apocynin on oxygenation, reactive oxygen species (ROS) levels, and NO signaling in PPHN lambs. PPHN was induced in lambs by antenatal ligation of the ductus arteriosus 9 days prior to delivery. Lambs were treated with vehicle or apocynin (3 mg/kg intratracheally) at birth and then ventilated with 100% O2 for 24 h. A significant improvement in oxygenation was observed in apocynin-treated lambs after 24 h of ventilation. Contractility of isolated fifth-generation PA to norepinephrine was attenuated in apocynin-treated lambs. PA constrictions to NO synthase (NOS) inhibition with N-nitro-L-arginine were blunted in PPHN lambs; apocynin restored contractility to N-nitro-L-arginine, suggesting increased NOS activity. Intratracheal apocynin also enhanced PA relaxations to the eNOS activator A-23187 and to the NO donor S-nitrosyl-N-acetyl-penicillamine. Apocynin decreased the interaction between NADPH oxidase subunits p22 phox and p47 phox and decreased the expression of Nox2 and p22 phox in ventilated PPHN lungs. These findings were associated with decreased superoxide and 3-nitrotyrosine levels in the PA of apocynin-treated PPHN lambs. eNOS protein expression, endothelial NO levels, and tetrahydrobiopterin-to-dihydrobiopterin ratios were significantly increased in PA from apocynin-treated lambs, although cGMP levels did not significantly increase and phosphodiesterase-5 activity did not significantly decrease. NADPH oxidase inhibition with apocynin may improve oxygenation, in part, by attenuating ROS-mediated vasoconstriction and by increasing NOS activity. reactive oxygen species; NADPH oxidase inhibition; nitric oxide signaling WHEN THE PULMONARY CIRCULATION fails to respond to various stimuli at birth, such as increased PO 2 and ventilation, it does not undergo the shift from the high-resistance, low-flow state in utero to the low-resistance, high-flow system postnatally (16,25). This failure results in persistent pulmonary hypertension of the newborn (PPHN) and is associated with impaired pulmonary gas exchange and oxygenation. Clinical strategies, such as mechanical ventilation with high concentrations of O 2 to correct hypoxemia and inhaled nitric oxide (NO), are commonly used to promote pulmonary vasodilation, but sustained improvement is not observed in ϳ40% of patients with PPHN (21). Hyperoxic ventilation also promotes formation of reactive oxygen species (ROS), such as superoxide anions, increases pulmonary artery (PA) contra...

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Apocynin-induced vasodilation involves Rho kinase inhibition but not NADPH oxidase inhibition

Cited by 82 publications

References 30 publications

NADPH oxidase has a directional response to shear stress

NADPH oxidase has a directional response to shear stress

Oxidative Stress and Endothelial Dysfunction in Aortas of Aged Spontaneously Hypertensive Rats by NOX1/2 Is Reversed by NADPH Oxidase Inhibition

Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

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