NAD(P)H-dependent superoxide production in platelets: The role of angiotensin II and protein kinase C

Plumb, Richard D.; El-Sherbeeny, Nagla A.; Dixon, Lana; Hughes, Sinead M.; Devine, Adrian; Leahey, William J.; McVeigh, Gary E.

doi:10.1016/j.clinbiochem.2005.04.012

Cited by 19 publications

(19 citation statements)

References 31 publications

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“…This may be secondary to decreased activation of NADPH oxidase as demonstrated previously by our group [14,15] and others [29]. Although previous studies have shown that lipidlowering alone can produce this improvement in ROS levels [29], we found no significant relationship between lipid alteration and decreased levels of oxidative stress in our present study.…”

Section: Discussioncontrasting

confidence: 74%

“…Rac is an integral part of the NADPH oxidase system, being crucial to the conformational changes that are necessary following activation and hence O 2 ᭹− release [13,14]. Therefore the decrease in Rac detected in the cell membranes may have lead to a reduction in the ability of NADPH oxidase to form O 2 ᭹− with statin therapy.…”

Section: Discussionmentioning

confidence: 97%

“…Basal release of superoxide, determined as chemiluminescence units/min, was recorded for up to 20 min to achieve a steady state. This method was used to determine O 2 ᭹− release from platelet samples containing diluent and lucigenin (Native sample), 5 μl of 500 μmol/l l-NAME (l-NAME sample) and from a sample containing 10 μl of 100 μM DPI (diphenyleneiodonium) and 1 mmol/l quinacrine (DPI/Quinacrine sample) [14,15]. The plateau height of the DPI/Quinacrine curve was subtracted from the native and the l-NAME curves.…”

Section: Measurement Of Platelet O 2 ᭹− Releasementioning

confidence: 99%

“…NO production by eNOS (endothelial NO synthase) has been shown to be reduced by Rho in several models [12], whereas the primary source of O 2 ᭹− , namely NADPH oxidase, depends on Rac for conformational change and subsequent activation [13,14].…”

Section: Introductionmentioning

confidence: 98%

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Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia

et al. 2009

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In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator NO and harmful superoxide free radicals. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac. By altering the membrane association of these molecules, statins affect intracellular positioning and hence activity of a multitude of substances. These include eNOS(endothelial NO synthase), which produces NO (inhibited by Rho), and NADPH oxidase, which produces superoxide (dependent on Rac). Statins may improve endothelial function by enhancing production of NO while decreasing superoxide production. A total of 40 hypercholesterolaemic patients were randomized to treatment with either atorvastatin or placebo; 20 normolipidaemic patients were also studied. Platelet nitrite, NO and superoxide were examined as was the cellular distribution of the GTPases Rho and Rac at baseline and after 8 weeks of treatment.Following atorvastatin therapy, platelet NO was increased (3.2 pmol/10(8) platelets) and superoxide output was attenuated [-3.4 pmol min(-1) (10(8) platelets)(-1)] when compared with placebo. The detection of both Rho and Rac was significantly reduced in the membranes of platelets, implying reduced activity. In conclusion, the results of the present study show altered NO/superoxide production following statin therapy. A potential mechanism for this is the change in the distribution of intracellular GTPases, which was considered to be secondary to decreases in isoprenoid intermediates, suggesting that the activity of the former had been affected by atorvastatin.

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 97%

Section: Measurement Of Platelet O 2 ᭹− Releasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia

et al. 2009

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“…ROS generation through mechanisms possibly involving an NADPH oxidase has also been reported in megakaryocyte cell lines (714,804). NOX2 appears to be the isoform expressed in platelets based on Western blots, where immunoreactivity toward p47 phox , p67 phox , and p22 phox (489,804) as well as NOX2 (708) are found. This is compatible with functional data from antibody-induced lysis of platelets, which is reduced in NOX2-deficient mice, strongly suggesting the presence of NOX2 (650).…”

Section: Plateletsmentioning

confidence: 95%

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Bedard¹,

Krause²

2007

Physiological Reviews

5,931

117

5,778

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For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX actvity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.

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The anti-platelet effects of apocynin in mice are not mediated by inhibition of NADPH oxidase activity

Dharmarajah

Arthur

Sobey

et al. 2010

Naunyn-Schmied Arch Pharmacol

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Apocynin, or a (myelo)peroxidase-derived product thereof, is a powerful inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Apocynin has also been shown to prevent aggregation of platelets in response to agonists such as collagen and thrombin. The aims of this study were to establish whether NADPH oxidase activity is required for aggregation of murine platelets to collagen and other agonists and whether the anti-aggregatory effects of apocynin are due to an inhibitory action against this enzyme. Washed platelets were isolated from male C57BL6 (wild-type), Nox2-deficient (Nox2(-/y )), and p47phox-deficient (p47phox(-/-)) mice for assessment of aggregation and NADPH oxidase subunit (Nox2, p47phox) expression. Collagen and U46619 elicited aggregation of murine platelets, and these responses were inhibited by apocynin at concentrations ≥100 μM. By contrast, aggregations to a direct protein kinase C activator, phorbol-12,13-dibutyrate, were insensitive to apocynin. Immunoblotting of platelet protein homogenates from wild-type mice with anti-Nox2 or p47phox antibodies revealed strong bands at 58 and 50 kDa, respectively. While expression of these immunoreactive bands was greatly diminished in platelets from Nox2(-/y ) and p47phox(-/-) mice, collagen still elicited aggregations that were similar to those observed in platelets from wild-types. Moreover, apocynin was an equally effective inhibitor of aggregation in platelets from all three mouse strains. In conclusion, these data suggest that NADPH oxidase-derived reactive oxygen species play no role in the aggregation response of washed murine platelets to collagen. Thus, our observation that apocynin is a powerful inhibitor of platelet aggregation raises further questions about the selectivity of this drug as an NADPH oxidase inhibitor.

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NAD(P)H-dependent superoxide production in platelets: The role of angiotensin II and protein kinase C

Cited by 19 publications

References 31 publications

Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia

Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

The anti-platelet effects of apocynin in mice are not mediated by inhibition of NADPH oxidase activity

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