Upregulation of Vascular NAD(P)H Oxidase Subunit gp91phox and Impairment of the Nitric Oxide Signal Transduction Pathway in Hypertension

Morawietz, Henning; Weber, Martina; Rueckschloss, Uwe; Lauer, Nadine; Hacker, Andreas; Kojda, Georg

doi:10.1006/bbrc.2001.5312

Cited by 65 publications

(35 citation statements)

References 49 publications

(43 reference statements)

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“…A key problem in this field is the lack of specific inhibitors and antibodies. Thus, although previous studies have shown increased NOX mRNA expression, 25,26 as well as increased NOX2 protein levels, 27 data on the aortic protein levels of all rodent vascular NOX isoforms in hypertensive animal models are missing. In addition, because of the lack of specific NADPH oxidase inhibitors, reliable pharmacological evidence that NADPH oxidases indeed play a functional role in this setting has not yet been possible.…”

Section: Discussionmentioning

confidence: 97%

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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Section: Discussionmentioning

confidence: 97%

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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“…54 In addition, increased Nox activity has been observed in different animal models of hypertension including ATII infusion, 14,55,56 deoxycorticosterone acetate (DOCA)-salt hypertension, 57 renovascular hypertension 58 and in spontaneously hypertensive rats. 59 Whether ROS derived from the Nox activation has a causal role in the development of hypertension was investigated by several animal studies using specific knockdown of Nox subunits. A major ROS source in response to ATII is Nox1 in the vascular smooth muscle layer.…”

Section: Ros Sources In Hypertension Nadph Oxidasesmentioning

confidence: 99%

Oxidative stress and endothelial dysfunction in hypertension

2011

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Systemic arterial hypertension is a highly prevalent cardiovascular risk factor that causes significant morbidity and mortality, and is becoming an increasingly common health problem because of the increasing longevity and prevalence of predisposing factors such as sedentary lifestyle, obesity and nutritional habits. Further complicating the impact of this disease, mild and moderate hypertension are usually asymptomatic, and their presence (and the subsequent increase in cardiovascular risk) is often unrecognized. The pathophysiology of hypertension involves a complex interaction of multiple vascular effectors including the activation of the sympathetic nervous system, of the renin-angiotensin-aldosterone system and of the inflammatory mediators. Subsequent vasoconstriction and inflammation ensue, leading to vessel wall remodeling and, finally, to the formation of atherosclerotic lesions as the hallmark of advanced disease. Oxidative stress and endothelial dysfunction are consistently observed in hypertensive subjects, but emerging evidence suggests that they also have a causal role in the molecular processes leading to hypertension. Reactive oxygen species (ROS) may directly alter vascular function or cause changes in vascular tone by several mechanisms including altered nitric oxide (NO) bioavailability or signaling. ROS-producing enzymes involved in the increased vascular oxidative stress observed during hypertension include the NADPH oxidase, xanthine oxidase, the mitochondrial respiratory chain and an uncoupled endothelial NO synthase. In the current review, we will summarize our current understanding of the molecular mechanisms in the development of hypertension with an emphasis on oxidative stress and endothelial dysfunction.

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“…In contrast, gp91 phox expression was knocked down by antisense oligos in resistance arteries from humans, and this led to abrogation of ROS production, whereas Nox1 expression was not detected here (327). The role of gp91 phox (Nox2) in hypertension was described by Morawietz et al (219), who showed that tenfold-elevated mRNA levels in the aorta were associated with threefold elevated levels of O 2 и-anion production in stroke-prone SHRs (SHR15) (219). In SHR15 rats, a decreased response to ACh, NO-donor (S-nitroso-N-acetyld, l-penicillamine), and organic nitrate (glyceryl trinitrate) was found, compared with an age-matched wild-type control, Wistar rats (WIS15).…”

Section: Nistala Et Al 2062mentioning

confidence: 99%