Enhanced platelet release of superoxide anion in systemic hypertension

Germanò, Giuseppe; Sanguigni, Valerio; Pignatelli, Pasquale; Caccese, Daniela; Lenti, Luisa; Ragazzo, M.; Lauro, Renato; Violi, Francesco

doi:10.1097/00004872-200406000-00016

Cited by 39 publications

(23 citation statements)

References 27 publications

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“…32 Other authors show that patients with hypertension show an enhanced oxidative stress with formation of O 2 À in platelets that was not dependent on blood pressure but could be mediated by AT1 receptors through NADPH oxidase activation probably, because patients treated with ARB irbesartan showed a decrease in platelet O 2 À production. 33 Our results are coherent with this observation as our hypertensive patients also showed an enhanced oxidative stress in leucocytes. As leucocytes have receptors type 1 on their membrane, the effect of eprosartan upon the oxidative stress could be attributable to the blockage of these receptors of AT II.…”

Section: Discussionsupporting

confidence: 91%

Effects of eprosartan on mitochondrial membrane potential and H2O2 levels in leucocytes in hypertension

et al. 2008

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We investigated whether circulating leucocytes from hypertensive patients exhibit more spontaneous, stimulated hydrogen peroxide (H 2 O 2 ) production and greater mitochondrial membrane potential (Dw) than those from normotensive individuals. We also investigated the effects of oral treatment with the angiotensin II (AT II) type 1 receptor blocker eprosartan (600 mg day À1) on these markers of oxidative stress. In 25 hypertensive patients and 28 healthy volunteers, spontaneous H 2 O 2 formation was measured by flow cytometry after preincubation of buffy coat-leucocytes from fresh peripheral venous blood at 37 1C with 2 0 ,7 0 dichlorofluorescein. Stimulation of H 2 O 2 formation by circulating leucocytes was elicited by the addition of tert-butylhydroperoxide (tBHP). Dw was determined by flow cytometry after the addition of tetramethylrhodamine methyl ester (TMRM). Compared with healthy individuals, lymphocytes from hypertensive patients exhibited higher Dw (12.28±3.20 vs 16.25±2.88 arbitrary fluorescence units (AFU), respectively; Po0.001) and greater spontaneous H 2 O 2 production (4.75 ± 5.15 vs 8.98 ± 9.97 AFU, respectively; Po0.05). tBHP stimulation was associated with higher H 2 O 2 levels in circulating leucocytes in patients with uncorrected hypertension than in normotensive individuals. H 2 O 2 overproduction was corrected by eprosartan treatment. These results suggest that oxidative stress could be important in the pathogenesis of hypertension. Furthermore, measurement of leucocyte oxidant activities may be useful for the evaluation of oxidative stress, which may be reduced with the use of antihypertensive drugs. Our results demonstrate that treatment of hypertension with eprosartan normalizes blood pressure and corrects oxidative disturbances, suggesting that leucocytes could be a target for this drug.

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Section: Discussionsupporting

confidence: 91%

Effects of eprosartan on mitochondrial membrane potential and H2O2 levels in leucocytes in hypertension

et al. 2008

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“…Based on a study in the aorta of hyperlipidemic rabbits where AT1-R blockade abrogated vascular superoxide generation from NADH oxidase [9], and previous findings in our model that AT1-R activation mediates the leukocyte adhesion and oxidative stress in postcapillary venules [36] it is conceivable that the vascular and perhaps leukocyte NAD(P)H oxidase is activated through an AT1-R receptor-dependent pathway. Although platelet superoxide release can be stimulated by angiotensin II acting though AT1-R activation [37], platelet AT1-R does not appear to participate in the thrombogenic responses in our model [38]. Consequently, the activation of platelet NAD(P)H oxidase may involve an alternative pathway such as CD40L [39], which has also been implicated in hypercholesterolemia-induced inflammation [40,41].…”

Section: Discussionmentioning

confidence: 78%

Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia

Stokes

Russell

Jennings

et al. 2007

Free Radical Biology and Medicine

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Elevated cholesterol levels promote pro-inflammatory and prothrombogenic responses in venules and impaired endothelium-dependent arteriolar dilation. Although NAD(P)H oxidase-derived superoxide has been implicated in the altered vascular responses to hypercholesterolemia, it remains unclear whether this oxidative pathway mediates the associated arteriolar dysfunction and platelet adhesion in venules. Platelet and leukocyte adhesion in cremasteric postcapillary venules, and arteriolar dilation responses to acetylcholine were monitored in wild-type (WT), Cu,Zn-superoxide dismutase transgenic (SOD-TgN) and NAD(P)H oxidase-knockout (gp91 phox-/-) mice placed on normal (ND) or high cholesterol (HC) diet for 2 wk. HC elicited increased platelet and leukocyte adhesion in WT mice, versus ND. Cytosolic subunits of NAD(P)H oxidase (p47phox and p67phox) were expressed in platelets. This was not altered by hypercholesterolemia, however platelets and leukocytes from HC mice exhibited elevated generation of reactive oxygen species when compared to ND mice. Hypercholesterolemia-induced leukocyte recruitment was attenuated in SOD-TgN-HC and gp91 phox-/--HC mice. Recruitment of platelets derived from WT-HC mice in venules of SODTgN-HC or gp91 phox-/--HC recipients was comparable to ND levels. Adhesion of SOD-TgN-HC platelets paralleled the leukocyte response and was attenuated in SOD-TgN-HC recipients, but not in WT-HC recipients. However, gp91 phox-/--HC platelets exhibited low levels of adhesion comparable to WT-ND in both hypercholesterolemic gp91 phox-/-and WT recipients. Arteriolar dysfunction was evident in WT-HC mice, compared to WT-ND. Overexpression of SOD or, to a lesser extent, gp91 phox deficiency, restored arteriolar vasorelaxation responses towards WT-ND levels. These findings reveal a novel role for platelet-associated NAD(P)H oxidase in producing the thrombogenic phenotype in hypercholesterolemia and demonstrate that NAD(P)H oxidase-derived superoxide mediates the HC-induced arteriolar dysfunction.

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“…In patients with heart failure, a TNF-␣-induced increase in platelet ROS generation has been suggested to contribute to the deterioration of cardiovascular function (186). Similarly, hypertensive patients have an increased platelet NADPH oxidase activity (301). Platelet NOX has also been implicated in the development of nitrate tolerance through the inactivation of nitric oxide by superoxide (598).…”

Section: Plateletsmentioning

confidence: 99%

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

Bedard¹,

Krause²

2007

Physiological Reviews

5,834

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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Enhanced platelet release of superoxide anion in systemic hypertension

Abstract: Patients with hypertension showed an enhanced formation of O2 in platelets that was not dependent on blood pressure but could be mediated by AT1 receptors via NADPH oxidase activation.

Cited by 39 publications

References 27 publications

Effects of eprosartan on mitochondrial membrane potential and H2O2 levels in leucocytes in hypertension

Effects of eprosartan on mitochondrial membrane potential and H2O2 levels in leucocytes in hypertension

Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia

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

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