DHEA attenuates PDGF-induced phenotypic proliferation of vascular smooth muscle A7r5 cells through redox regulation

Urata, Yoshishige; Goto, Shinji; Kawakatsu, Miho; Yodoi, Junji; Eto, Masato; Akishita, Masahiro; Kondo, Takahito

doi:10.1016/j.bbrc.2010.04.125

Cited by 12 publications

(6 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For Glrx and Cx3cl1, up- and downregulation, respectively, were even confirmed with RT-PCR. Contrary to our results, where upregulation of Glrx was associated with increased proliferation of A7r5 VSMCs, upregulation of Glrx has been linked to decreased proliferation of A7r5 VSMCs, as reported by Urata et al [128]. In pulmonary artery SMCs and in human lung cancer tissue, Glrx expression showed an inverse correlation with proliferation [129, 130].…”

Section: Discussioncontrasting

confidence: 95%

Gene expression profiles and signaling mechanisms in α2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells

Huhtinen

Hongisto²,

Laiho

et al. 2017

BMC Syst Biol

View full text Add to dashboard Cite

Backgroundα2-adrenoceptors are important regulators of vascular tone and blood pressure. Regulation of cell proliferation is a less well investigated consequence of α2-adrenoceptor activation. We have previously shown that α2B-adrenoceptor activation stimulates proliferation of vascular smooth muscle cells (VSMCs). This may be important for blood vessel development and plasticity and for the pathology and therapeutics of cardiovascular disorders. The underlying cellular mechanisms have remained mostly unknown. This study explored pathways of regulation of gene expression and intracellular signaling related to α2B-adrenoceptor-evoked VSMC proliferation.ResultsThe cellular mechanisms and signaling pathways of α2B-adrenoceptor-evoked proliferation of VSMCs are complex and include redundancy. Functional enrichment analysis and pathway analysis identified differentially expressed genes associated with α2B-adrenoceptor-regulated VSMC proliferation. They included the upregulated genes Egr1, F3, Ptgs2 and Serpine1 and the downregulated genes Cx3cl1, Cav1, Rhoa, Nppb and Prrx1. The most highly upregulated gene, Lypd8, represents a novel finding in the VSMC context. Inhibitor library screening and kinase activity profiling were applied to identify kinases in the involved signaling pathways. Putative upstream kinases identified by two different screens included PKC, Raf-1, Src, the MAP kinases p38 and JNK and the receptor tyrosine kinases EGFR and HGF/HGFR. As a novel finding, the Src family kinase Lyn was also identified as a putative upstream kinase.Conclusionsα2B-adrenoceptors may mediate their pro-proliferative effects in VSMCs by promoting the activity of bFGF and PDGF and the growth factor receptors EGFR, HGFR and VEGFR-1/2. The Src family kinase Lyn was also identified as a putative upstream kinase. Lyn is known to be expressed in VSMCs and has been identified as an important regulator of GPCR trafficking and GPCR effects on cell proliferation. Identified Ser/Thr kinases included several PKC isoforms and the β-adrenoceptor kinases 1 and 2. Cross-talk between the signaling mechanisms involved in α2B-adrenoceptor-evoked VSMC proliferation thus appears to involve PKC activation, subsequent changes in gene expression, transactivation of EGFR, and modulation of kinase activities and growth factor-mediated signaling. While many of the identified individual signals were relatively small in terms of effect size, many of them were validated by combining pathway analysis and our integrated screening approach.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-017-0439-8) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussioncontrasting

confidence: 95%

Gene expression profiles and signaling mechanisms in α2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells

Huhtinen

Hongisto²,

Laiho

et al. 2017

BMC Syst Biol

View full text Add to dashboard Cite

show abstract

“…These results were confirmed in vivo by a decrease of vascular remodeling in the rat model of ballooninjured carotid treated with DHEA, showing the potential of DHEA as therapeutic for restenosis. It was demonstrated that PDGF-induced proliferation is inhibited by DHEA through a GSH/GRX1 mechanism [75], GRX1 playing an important role in PDGF signal regulation by a downregulation of tyrosine phosphorylation of the PDGF receptor [76]. This is in agreement with previous findings showing that GRX1 and γ-Glutamylcysteine synthetase (γ-GCS) display a PPAR response element in their promoter and are up-regulated at the transcriptional level by PPARα.…”

Section: Dhea Anti-proliferative Propertiessupporting

confidence: 89%

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

Paulin¹

2013

J Steroids Horm Sci

View full text Add to dashboard Cite

“…We used rat A7r5 cells for this study [17]. The cells were cultured in DMEM supplemented with 10% FBS at 37°C under a humidified atmosphere of 5% CO 2 .…”

Section: Cell Culture and Gamma-ray Irradiationmentioning

confidence: 99%

Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation

Yoshida

Goto

Kawakatsu

et al. 2012

Free Radical Research

Self Cite

148

View full text Add to dashboard Cite

Several recent studies have suggested that the reactive oxygen species (ROS) generated from mitochondria contribute to genomic instability after exposure of the cells to ionizing radiation, but the mechanism of this process is not yet fully understood. We examined the hypothesis that irradiation induces mitochondrial dysfunction to cause persistent oxidative stress, which contributes to genomic instability. After the exposure of cells to 5 Gy gamma-ray irradiation, we found that the irradiation induced the following changes in a clear pattern of time courses. First, a robust increase of intracellular ROS levels occurred within minutes, but the intracellular ROS disappeared within 30 minutes. Then the mitochondrial dysfunction was detected at 12 hours after irradiation, as indicated by the decreased activity of NADH dehydrogenase (Complex I), the most important enzyme in regulating the release of ROS from the mitochondrial electron transport chain (ETC). Finally, a significant increase of ROS levels in the mitochondria and the oxidation of mitochondrial DNA were observed in cells at 24 hours or later after irradiation.Although further experiments are required, results in this study support the hypothesis that mitochondrial dysfunction causes persistent oxidative stress that may contribute to promote radiation-induced genomic instability.2

show abstract

DHEA attenuates PDGF-induced phenotypic proliferation of vascular smooth muscle A7r5 cells through redox regulation

Cited by 12 publications

References 17 publications

Gene expression profiles and signaling mechanisms in α2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells

Gene expression profiles and signaling mechanisms in α2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells

Dehydroepiandrosterone, Over-studied but Under-used in the Treatment of Vascular Remodeling Diseases

Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation

Contact Info

Product

Resources

About