Negative Regulation of NADPH Oxidase 4 by Hydrogen Peroxide-inducible Clone 5 (Hic-5) Protein

Desai, Leena P.; Zhou, Yong; Estrada, Aida V.; Ding, Qiang; Cheng, Guangjie; Collawn, James F.; Thannickal, Victor J.

doi:10.1074/jbc.m114.562249

Cited by 45 publications

(40 citation statements)

References 43 publications

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“…This model suggests that disruption of isometric tension could be an important therapeutic strategy for fibrotic diseases that occur in skin, as well as in parenchymal organs such as the lung and liver. Our data differ from those of a recent study on pulmonary fibroblasts, in which depletion of Hic-5 augmented both basal α-SMA expression and TGF-β induction of α-SMA after 24 h (Desai et al, 2014). However, when we knocked down Hic-5 in IMR-90 cells with two different siRNA duplexes, we observed the opposite result, namely that the induction of α-SMA after 24 h and 48 h of TGF-β stimulation (2 ng/ml) was reduced in Hic-5-deficient cells.…”

Section: Discussioncontrasting

confidence: 56%

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-β on myofibroblast differentiation remains a crucial area of investigation. We report here that the focal adhesion protein, Hic-5 (also known as TGFB1I1), is required for the mechanically dependent generation of stress fibers in response to TGF-β. Successful generation of stress fibers promotes the nuclear localization of the transcriptional co-factor MRTF-A (also known as MKL1), and this correlates with the mechanically dependent induction of α smooth muscle actin (α-SMA) and Hic-5 in response to TGF-β. As a consequence of regulating stress fiber assembly, Hic-5 is required for the nuclear accumulation of MRTF-A and the induction of α-SMA as well as cellular contractility, suggesting a crucial role for Hic-5 in myofibroblast differentiation. Indeed, the expression of Hic-5 was transient in acute wounds and persistent in pathogenic scars, and Hic-5 colocalized with α-SMA expression in vivo. Taken together, these data suggest that a mechanically dependent feed-forward loop, elaborated by the reciprocal regulation of MRTF-A localization by Hic-5 and Hic-5 expression by MRTF-A, plays a crucial role in myofibroblast differentiation in response to TGF-β.

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Section: Discussioncontrasting

confidence: 56%

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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“…Post-transcriptional regulation of Nox4 in aging (60) and post-translational regulation of Nox4 in aging (14) were also reported. Finally, Sanders et al (45) reported that despite its decrease at the global level, increased association of histone H4K16 in replicative senescent fibroblasts upregulates Nox4 expression, indicating an epigenetic regulation of Nox4 in aging.…”

Section: Discussionmentioning

confidence: 99%

NOX4 NADPH Oxidase-Dependent Mitochondrial Oxidative Stress in Aging-Associated Cardiovascular Disease

Vendrov

Smith

et al. 2015

Antioxidants & Redox Signaling

174

197

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Aims: Increased oxidative stress and vascular inflammation are implicated in increased cardiovascular disease (CVD) incidence with age. We and others demonstrated that NOX1/2 NADPH oxidase inhibition, by genetic deletion of p47phox, in Apoe -/ -mice decreases vascular reactive oxygen species (ROS) generation and atherosclerosis in young age. The present study examined whether NOX1/2 NADPH oxidases are also pivotal to aging-associated CVD. Results: Both aged (16 months) Apoe -/ -and Apoe -/ -/p47phox -/ -mice had increased atherosclerotic lesion area, aortic stiffness, and systolic dysfunction compared with young (4 months) cohorts. Cellular and mitochondrial ROS (mtROS) levels were significantly higher in aortic wall and vascular smooth muscle cells (VSMCs) from aged wild-type and p47phox -/ -mice. VSMCs from aged mice had increased mitochondrial protein oxidation and dysfunction and increased vascular cell adhesion molecule 1 expression, which was abrogated with (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) treatment. NOX4 expression was increased in the vasculature and mitochondria of aged mice and its suppression with shRNA in VSMCs from aged mice decreased mtROS levels and improved function. Increased mtROS levels were associated with enhanced mitochondrial NOX4 expression in aortic VSMCs from aged subjects, and NOX4 expression levels in arterial wall correlated with age and atherosclerotic severity. Aged Apoe -/ -mice treated with MitoTEMPO and 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo [4,3-c]pyridine-3,6(2H,5H)-dione had decreased vascular ROS levels and atherosclerosis and preserved vascular and cardiac function. Innovation and Conclusion: These data suggest that NOX4, but not NOX1/2, and mitochondrial oxidative stress are mediators of CVD in aging under hyperlipidemic conditions. Regulating NOX4 activity/expression and using mitochondrial antioxidants are potential approaches to reducing aging-associated CVD.

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“…Techniques used for estimation of steadystate mRNA levels are similar to those described eleswhere (9). The primers sequences used are as in Table E3.…”

Section: Real-time Pcrmentioning

confidence: 99%

“…Culture techniques are similar to those described earlier by our group (9). Briefly, the fibroblasts were cultured in DMEM (Life Technologies, Grand Island, NY) supplemented with 10% FBS, 100 U/ml penicillin, 100 mg/ml streptomycin, and 250 mg/ml amphotericin-B and were incubated at 37 8 C in 5% CO 2 and 95% air.…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

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Novel Mechanisms for the Antifibrotic Action of Nintedanib

Rangarajan

Kurundkar

et al. 2016

Am J Respir Cell Mol Biol

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180

121

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Idiopathic pulmonary fibrosis (IPF) is a disease with relentless course and limited therapeutic options. Nintedanib (BIBF-1120) is a multiple tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of IPF. The precise antifibrotic mechanism(s) of action of nintedanib, however, is not known. Therefore, we studied the effects of nintedanib on fibroblasts isolated from the lungs of patients with IPF. Protein and gene expression of profibrotic markers were assessed by Western immunoblotting and real-time PCR. Autophagy markers and signaling events were monitored by biochemical assays, Western immunoblotting, microscopy, and immunofluorescence staining. Silencing of autophagy effector proteins was achieved with small interfering RNAs. Nintedanib down-regulated protein and mRNA expression of extracellular matrix (ECM) proteins, fibronectin, and collagen 1a1 while inhibiting transforming growth factor (TGF)-b1-induced myofibroblast differentiation. Nintedanib also induced beclin-1-dependent, ATG7-independent autophagy. Nintedanib's ECM-suppressive actions were not mediated by canonical autophagy. Nintedanib inhibited early events in TGF-b signaling, specifically tyrosine phosphorylation of the type II TGF-b receptor, activation of SMAD3, and p38 mitogen-activated protein kinase. Nintedanib down-regulates ECM production and induces noncanonical autophagy in IPF fibroblasts while inhibiting TGF-b signaling. These mechanisms appear to be uncoupled and function independently to mediate its putative antifibrotic effects.

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Negative Regulation of NADPH Oxidase 4 by Hydrogen Peroxide-inducible Clone 5 (Hic-5) Protein

Cited by 45 publications

References 43 publications

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

NOX4 NADPH Oxidase-Dependent Mitochondrial Oxidative Stress in Aging-Associated Cardiovascular Disease

Novel Mechanisms for the Antifibrotic Action of Nintedanib

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