Unrestrained p38 MAPK Activation in
            <i>Dusp1/4</i>
            Double-Null Mice Induces Cardiomyopathy

Auger‐Messier, Mannix; Accornero, Federica; Goonasekera, Sanjeewa A.; Bueno, Orlando F.; Lorenz, John N.; Berlo, Jop H. van; Willette, Robert N.; Molkentin, Jeffery D.

doi:10.1161/circresaha.112.272963

Cited by 84 publications

(79 citation statements)

References 37 publications

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“…As our data suggest, silencing an individual DUSP may lead to compensation by other isoforms. This effect has been reported in cardiomyocytes, where redundancy of DUSP1 and DUSP4 has been demonstrated (Auger-Messier et al, 2013). Interestingly, bexarotene did not affect the responses of SMC to PDGF.…”

Section: Discussionsupporting

confidence: 77%

Activation of the Retinoid X Receptor Modulates Angiotensin II-Induced Smooth Muscle Gene Expression and Inflammation in Vascular Smooth Muscle Cells

et al. 2014

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The retinoid X receptor (RXR) partners with numerous nuclear receptors, such as the peroxisome proliferator activated receptor (PPAR) family, liver X receptors (LXRs), and farnesoid X receptor (FXR). Although each heterodimer can be activated by specific ligands, a subset of these receptors, defined as permissive nuclear receptors, can also be activated by RXR agonists known as rexinoids. Many individual RXR heterodimers have beneficial effects in vascular smooth muscle cells (SMCs). Because rexinoids can potently activate multiple RXR pathways, we hypothesized that treating SMCs with rexinoids would more effectively reverse the pathophysiologic effects of angiotensin II than an individual heterodimer agonist. Cultured rat aortic SMCs were pretreated with either an RXR agonist (bexarotene or 9-cis retinoic acid) or vehicle (dimethylsulfoxide) for 24 hours before stimulation with angiotensin II. Compared with dimethylsulfoxide, bexarotene blocked angiotensin II-induced SM contractile gene induction (calponin and smooth muscle-a-actin) and protein synthesis ([ 3 H]leucine incorporation). Bexarotene also decreased angiotensin II-mediated inflammation, as measured by decreased expression of monocyte chemoattractant protein-1 (MCP-1). Activation of p38 mitogen-activated protein (MAP) kinase but not extracellular signal-related kinase (ERK) or protein kinase B (Akt) was also blunted by bexarotene. We compared bexarotene to five agonists of nuclear receptors (PPARa, PPARg, PPARd, LXR, and FXR). Bexarotene had a greater effect on calponin reduction, MCP-1 inhibition, and p38 MAP kinase inhibition than any individual agonist. PPARg knockout cells demonstrated blunted responses to bexarotene, indicating that PPARg is necessary for the effects of bexarotene. These data demonstrate that RXR is a potent modulator of angiotensin II-mediated responses in the vasculature, partially through inhibition of p38.

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Section: Discussionsupporting

confidence: 77%

Activation of the Retinoid X Receptor Modulates Angiotensin II-Induced Smooth Muscle Gene Expression and Inflammation in Vascular Smooth Muscle Cells

et al. 2014

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“…Dusp4 is strongly overexpressed in Treg cells, which might plausibly account for dampened TCR-induced signals in Treg cells. We thus analyzed responses in cells from Dusp4-deficient mice (41), in which Treg cells are present in normal proportions and which have no autoimmune or immune dysregulation manifestations. Contrary to our hypothesis, ERK phosphorylation dynamics in Dusp4-deficient T cells proved essentially superimposable to those of cocultured WT cells, for both Treg and Tconv (Fig.…”

Section: Dusp4 Modulates Specific Facets Of Treg Function and Homeostmentioning

confidence: 99%

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Yan

Farache

Mingueneau

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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FoxP3+ T regulatory (Treg) cells have a fundamental role in immunological tolerance, with transcriptional and functional phenotypes that demarcate them from conventional CD4+ T cells (Tconv). Differences between these two lineages in the signaling downstream of T-cell receptor-triggered activation have been reported, and there are different requirements for some signaling factors. Seeking a comprehensive view, we found that Treg cells have a broadly dampened activation of several pathways and signaling nodes upon TCR-mediated activation, with low phosphorylation of CD3ζ, SLP76, Erk1/2, AKT, or S6 and lower calcium flux. In contrast, STAT phosphorylation triggered by interferons, IL2 or IL6, showed variations between Treg and Tconv in magnitude or choice of preferential STAT activation but no general Treg signaling defect. Much, but not all, of the Treg/Tconv difference in TCR-triggered responses could be attributed to lower responsiveness of antigen-experienced cells with CD44hi or CD62Llo phenotypes, which form a greater proportion of the Treg pool. Candidate regulators were tested, but the Treg/Tconv differential could not be explained by overexpression in Treg cells of the signaling modulator CD5, the coinhibitors PD-1 and CTLA4, or the regulatory phosphatase DUSP4. However, transcriptome profiling in Dusp4-deficient mice showed that DUSP4 enhances the expression of a segment of the canonical Treg transcriptional signature, which partially overlaps with the TCR-dependent Treg gene set. Thus, Treg cells, likely because of their intrinsically higher reactivity to self, tune down TCR signals but seem comparatively more attuned to cytokines or other intercellular signals.

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“…Cardiac-specific overexpression of DUSP1 results in suppression of ERK, JNK, and p38 signaling and blunting of cardiac hypertrophy in response to pressure overload (42). Dual knockout of DUSP1 and -4 was recently shown to stimulate p38 signaling and cause cardiomyopathy (43). DUSP6 is a cytoplasmic phosphatase that is thought to specifically regulate ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy

Ferguson

Harrison

Jeong

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

100

104

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Cardiac hypertrophy is a strong predictor of morbidity and mortality in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors have been shown to suppress cardiac hypertrophy through mechanisms that remain poorly understood. We report that class I HDACs function as signal-dependent repressors of cardiac hypertrophy via inhibition of the gene encoding dual-specificity phosphatase 5 (DUSP5) DUSP5, a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. Inhibition of DUSP5 by class I HDACs requires activity of the ERK kinase, mitogenactivated protein kinase kinase (MEK), revealing a self-reinforcing mechanism for promotion of cardiac ERK signaling. In cardiac myocytes treated with highly selective class I HDAC inhibitors, nuclear ERK1/2 signaling is suppressed in a manner that is absolutely dependent on DUSP5. In contrast, cytosolic ERK1/2 activation is maintained under these same conditions. Ectopic expression of DUSP5 in cardiomyocytes results in potent inhibition of agonist-dependent hypertrophy through a mechanism involving suppression of the gene program for hypertrophic growth. These findings define unique roles for class I HDACs and DUSP5 as integral components of a regulatory signaling circuit that controls cardiac hypertrophy.

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Unrestrained p38 MAPK Activation in Dusp1/4 Double-Null Mice Induces Cardiomyopathy

Cited by 84 publications

References 37 publications

Activation of the Retinoid X Receptor Modulates Angiotensin II-Induced Smooth Muscle Gene Expression and Inflammation in Vascular Smooth Muscle Cells

Activation of the Retinoid X Receptor Modulates Angiotensin II-Induced Smooth Muscle Gene Expression and Inflammation in Vascular Smooth Muscle Cells

Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy

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