Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation☆

Freyhaus, Henrik ten; Huntgeburth, Michael; Wingler, Kirstin; Schnitker, Jessika; Bäumer, Anselm T.; Vantler, Marius; Bekhite, Mohamed M.; Wartenberg, Maria; Sauer, Heinrich; Rosenkranz, Stephan

doi:10.1016/j.cardiores.2006.01.022

Cited by 238 publications

(173 citation statements)

References 44 publications

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“…Multiple sources of ROS have been implicated in migration. The novel Nox inhibitor VAS2870 attenuates PDGF-induced migration (Ten Freyhaus et al 2006). Furthermore, in vivo studies have shown that remodeling is delayed in p47phox−/− mice and is completely abolished in mice lacking eNOS, suggesting that early remodeling requires NADPH oxidasederived ROS, while late remodeling is more dependent on ONOO • generated by eNOS (Castier et al 2005).…”

Section: Vascular Smooth Muscle Cell Migrationmentioning

confidence: 99%

“…Rapamycin, a relatively new immunosuppressant that acts on the protein synthesis mediator mTOR, inhibits PDGF-induced proliferation without affecting ROS production (Park et al 2005). Furthermore, although PDGF-induced migration is inhibited by the novel Nox inhibitor VAS2870, this inhibitor has no effect on DNA synthesis (Ten Freyhaus et al 2006). Whereas these latter observations could be used to support the concept that both ROS-sensitive and ROS-insensitive signaling pathways mediate PDGF-induced proliferation, we have not been able to demonstrate a requirement for ROS in PDGF-induced growth in these cells (unpublished observations).…”

Section: Vascular Smooth Muscle Proliferationmentioning

confidence: 99%

See 1 more Smart Citation

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

Papaharalambus

Griendling

2007

Trends in Cardiovascular Medicine

291

224

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The development of vascular disease has its origins in an initial insult to the vessel wall by biological or mechanical factors. The disruption of homeostatic mechanisms leads to alteration of the original architecture of the vessel and its biological responsiveness, contributing to acute or chronic diseases such as stroke, hypertension and atherosclerosis. Endothelial dysfunction, macrophage infiltration of the vessel wall, and proliferation and migration of smooth muscle cells all involve different types of reactive oxygen species, produced by various vessel wall components. Although basic science and animal research have clearly established the role of reactive oxygen species in the progression of vascular disease, the failure of clinical trials with antioxidant compounds has underscored the need for better antioxidant therapies and a more thorough understanding of the role of reactive oxygen species in cardiovascular physiology and pathology.The fundamental processes underlying the development of vascular diseases such as atherosclerosis, restenosis and hypertensive vascular remodeling have their origins in an initial insult to the vessel wall. Such an insult may arise from mechanical disruption that occurs during percutaneous coronary angioplasty or at regions of oscillatory shear stress, or it can result from biological causes, such as hypercholesterolemia, excess free radicals, diabetes, increased concentrations of plasma homocysteine, or infectious agents. Injury promotes disruption of the homeostatic mechanisms of the endothelial protective barrier, changing its natural properties, increasing its adhesiveness to leukocytes and altering its permeability. This endothelial dysfunction also leads to the formation of vasoactive molecules, which in turn induce inflammatory genes, inactivate nitric oxide (NO • ) and its protective functions, and activate matrix metalloproteinases, leading to extracellular matrix remodeling, and increased smooth muscle cell (VSMC) growth, migration and proliferation. Each of these processes contributes to thickening of the vessel wall or the formation of lesions that can lead to hypertension, acute myocardial infarction and stroke. Reactive Oxygen Species and Vascular InjuryIn the past decade a staggering amount of evidence implicates a common denominator, reactive oxygen species (ROS), in the development of most cardiovascular diseases (Figure 1). Superoxide (O 2 •− ) and hydrogen peroxide (H 2 O 2 ) are two of the most biologically important ROS in the cardiovascular system, and are produced in vascular cells by a number of oxidases, including the NADPH oxidases (Nox) and xanthine oxidase, lipoxygenases, cytochrome p450,

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Section: Vascular Smooth Muscle Cell Migrationmentioning

confidence: 99%

Section: Vascular Smooth Muscle Proliferationmentioning

confidence: 99%

Basic Mechanisms of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Injury

Papaharalambus

Griendling

2007

Trends in Cardiovascular Medicine

291

224

View full text Add to dashboard Cite

show abstract

“…VAS2870 (3-bezyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine] was discovered via a high-throughput screening assay specific for NAD(P)H oxidase activity at Vasopharm Biotech. Its unique property is that it can inhibit agonist-induced NAD(P)H activity but not the basal activity of this enzyme complex, suggesting specificity within the NAD(P)H oxidase family [e.g., Nox1 activation by PDGF is inhibited, but Nox4 activity at basal level in VSMCs is unaffected (322)]. However, a screening for Nox specificity has not been conducted.…”

Section: Phycobilinsmentioning

confidence: 99%

Redox Control of Renal Function and Hypertension

Nistala

Whaley‐Connell

Sowers

2008

Antioxidants & Redox Signaling

139

123

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“…10 Pharmacological inhibitors of Nox4 (VAS2870 and GKT136901) also prevented agonist-induced oxidative stress and inflammatory responses in cultured cells. 11,12 However, these observations are merely suggestive of Nox4 in vascular pathology and by no means establish cause and effect.…”

Section: Article See P 1217mentioning

confidence: 92%

“…First, in the study of Schroder et al, 14 vascular functional studies were performed in large conduit vessels (aorta) and in lung endothelial cells from Nox4-deficient mice, whereas many previous studies explored small arteries and cultured vascular smooth muscle cells. 3,5,9,10,11,17,18 Second, in Nox4 knockout mice, the gene deletion is global, and, accordingly, it is not entirely correct to implicate a vascular-specific pathology in a model in which there is a ubiquitous knockout. Third, the fact that it is only in challenged conditions that Nox4 knockout mice exhibit a vascular phenotype indicates a nonessential role of Nox4 in physiological conditions.…”

Section: Article See P 1217mentioning

confidence: 99%