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Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation☆
Abstract
OBJECTIVE: Reactive oxygen species (ROS) produced by NAD(P)H oxidases (Nox) play a significant role in the pathophysiology of cardiovascular diseases. Expression and activity of NAD(P)H oxidases are regulated by growth factors such as angiotensin II and platelet-derived growth factor (PDGF). We characterized the effects of the novel Nox inhibitor VAS2870 on PDGF-dependent ROS liberation and cellular events in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: PDGF-BB increased NAD(P)H oxidase activity (lucigenin-enhanced chemiluminescence) and intracellular ROS levels (detected by confocal laserscanning microscopy using 2,7-DCF) to 229+/-9% and 362+/-54% at 1 and 2 h, respectively. Preincubation with VAS2870 (10 and 20 microM) completely abolished PDGF-mediated NAD(P)H oxidase activation and ROS production. Since ROS are involved in various growth factor-induced cellular functions, the influence of VAS2870 on PDGF-induced DNA synthesis and chemotaxis was determined. PDGF promoted a 4.2+/-0.2-fold increase of VSMC migration (modified Boyden chamber, p<0.01) and increased DNA synthesis by maximally 3.2+/-0.4-fold (BrdU incorporation, p<0.01) in a concentration-dependent manner. Preincubation with VAS2870 (0.1-20 microM) did not affect PDGF-induced cell cycle progression. However, it abolished PDGF-dependent chemotaxis of VSMC in a concentration-dependent manner (100% inhibition at 10 microM). These findings were related to PDGF-dependent signaling events. Western blot analyses using phospho-specific antibodies revealed that the downstream signaling molecules Akt, Erk, and Src were activated by PDGF. However, VAS2870 blocked PDGF-dependent activation of Src, but not of Akt and Erk, in a concentration-dependent manner. CONCLUSIONS: VAS2870 effectively suppresses growth factor-mediated ROS liberation in VSMC. Furthermore, it completely inhibits PDGF-dependent VSMC migration, whereas it does not affect DNA synthesis. These divergent effects reflect the critical role of Src activity, which-in contrast to Akt and Erk-appears to be redox-sensitive and is absolutely required for PDGF-induced chemotaxis, but not cell cycle progression.
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“This scheme has been found to apply to virtually all the heme protein–mediated nitrite reduction reactions studied to date, including Hb (248, 447), Mb (247, 862), neuroglobin (Ngb) (932, 945), Cygb (182, 571, 780), cystathionine β-synthase (CBS) (149, 350), globin X (184), plant and cyanobacterial Hb (phytohemoglobins) (905, 946), flavohemoglobin (340), heme-albumin (43), cytochrome c (41), prot”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [932]
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“It was recently demonstrated that, as observed with other globins, deoxygenated Ngb can also reduce nitrite to NO (932, 945).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [932]
In the citing paper
“However, although initial experiments suggested VAS2870 to be Nox2-specific, it is definitely not [341,393,403,404].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [404]
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Metadata
- Authors
- TENFREYHAUS, H., HUNTGEBURTH, M., WINGLER, K., SCHNITKER, J., BAUMER, A., VANTLER, M., BEKHITE, M., WARTENBERG, M., SAUER, H., & ROSENKRANZ, S.
- Affiliations
- University of Cologne (DE)
- Vasopharm (Germany) (DE)
- Justus-Liebig-Universität Gießen (DE)
- Corresponding author
- ROSENKRANZ, S
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-07-15
- Volume
- 71
- Issue
- 2
- Pages
- 331-341
- ISSN
- 0008-6363 (ISSN-L)
- OpenAlex
- W2136386024
- Cited by
- 259
- References
- 46
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 4 · 2023: 8 · 2022: 7 · 2021: 13 · 2020: 15 · 2019: 15 · 2018: 13 · 2017: 14 · 2016: 9 · 2015: 19 · 2014: 22 · 2013: 24 · 2012: 22
- FWCI
- 7.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- VAS2870, platelet-derived growth factor, vascular smooth muscle cells, reactive oxygen species, cell proliferation, Src kinase, Akt, ERK, PDGF signaling, cell migration, DNA synthesis, cardiovascular disease, redox signaling, chemiluminescence, BrdU incorporation, immunofluorescence
- MeSH terms
- Becaplermin, Animals, Aorta, Thoracic, Benzoxazoles, Cell Survival, Cells, Cultured, Chemotaxis, DNA, Enzyme Inhibitors, Muscle, Smooth, Vascular, Platelet-Derived Growth Factor, Rats, Inbred WKY, Triazoles, Blotting, Western, Reactive Oxygen Species, src-Family Kinases, NADPH Oxidases, Proto-Oncogene Proteins c-sis, Myocytes, Smooth Muscle, Immunoprecipitation, Cell Proliferation, Rats
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