A novel p38 MAPK target dyxin is rapidly induced by mechanical load in the heart

Luosujärvi, Hanne; Aro, Jani; Tokola, Heikki; Leskinen, Hanna; Tenhunen, Olli; Skoumal, Réka; Szokodi, István; Ruskoaho, Heikki; Rysä, Jaana

doi:10.3109/08037050903464519

Cited by 8 publications

(11 citation statements)

References 26 publications

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“…The MKK3b, MKK6b and WT p38β adenoviruses have been described previously [20]. The ATF3–overexpressing adenovirus (serotype 5) was generated as previously described [21]. Briefly, a full-length coding region of ATF3 cDNA was subcloned into the SalI and HindIII sites of the pShuttle-CMV vector (Qbiogene Inc, Montreal, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA from left ventricular tissue was isolated by the guanidine thiocyanate-CsCl method and from cultured cardiomyocytes with TRIzol Reagent according to the manufacturer's protocol (Invitrogen) by using Phase Lock Gel system (Eppendorf AG, Hamburg, Germany) [21]. Rat ATF3, BNP, ANP, IL-6, PAI-1, osteopontin (OSP), bone morphogenetic protein-2 (BMP-2) and ribosomal 18S mRNA levels were measured by real-time RT-qPCR as previously described [12].…”

Section: Methodsmentioning

confidence: 99%

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Characterization of the Regulatory Mechanisms of Activating Transcription Factor 3 by Hypertrophic Stimuli in Rat Cardiomyocytes

et al. 2014

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AimsActivating transcription factor 3 (ATF3) is a stress-activated immediate early gene suggested to have both detrimental and cardioprotective role in the heart. Here we studied the mechanisms of ATF3 activation by hypertrophic stimuli and ATF3 downstream targets in rat cardiomyocytes.Methods and ResultsWhen neonatal rat cardiomyocytes were exposed to endothelin-1 (ET-1, 100 nM) and mechanical stretching in vitro, maximal increase in ATF3 expression occurred at 1 hour. Inhibition of extracellular signal-regulated kinase (ERK) by PD98059 decreased ET-1– and stretch–induced increase of ATF3 protein but not ATF3 mRNA levels, whereas protein kinase A (PKA) inhibitor H89 attenuated both ATF3 mRNA transcription and protein expression in response to ET-1 and stretch. To characterize further the regulatory mechanisms upstream of ATF3, p38 mitogen-activated protein kinase (MAPK) signaling was investigated using a gain-of-function approach. Adenoviral overexpression of p38α, but not p38β, increased ATF3 mRNA and protein levels as well as DNA binding activity. To investigate the role of ATF3 in hypertrophic process, we overexpressed ATF3 by adenovirus-mediated gene transfer. In vitro, ATF3 gene delivery attenuated the mRNA transcription of interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1), and enhanced nuclear factor-κB (NF-κB) and Nkx-2.5 DNA binding activities. Reduced PAI-1 expression was also detected in vivo in adult rat heart by direct intramyocardial adenovirus-mediated ATF3 gene delivery.ConclusionsThese data demonstrate that ATF3 activation by ET-1 and mechanical stretch is partly mediated through ERK and cAMP-PKA pathways, whereas p38 MAPK pathway is involved in ATF3 activation exclusively through p38α isoform. ATF3 activation caused induction of modulators of the inflammatory response NF-κB and Nkx-2.5, as well as attenuation of pro-fibrotic and pro-inflammatory proteins IL-6 and PAI-1, suggesting cardioprotective role for ATF3 in the heart.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Characterization of the Regulatory Mechanisms of Activating Transcription Factor 3 by Hypertrophic Stimuli in Rat Cardiomyocytes

et al. 2014

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“…LMCD1 levels increase in pressure overload, following MI and in response to AngII infusion [241, 242]. Transgenic over-expression of LMCD1 increases calcineurin activation in response to pressure overload and accentuates pathological remodeling in vivo , whereas depletion of LMCD1 blunts NFAT activation in vitro [242].…”

Section: Calcineurin Substrates Relevant To Cardiovascular Healthmentioning

confidence: 99%

Calcineurin signaling in the heart: The importance of time and place

Parra

Rothermel

2017

Journal of Molecular and Cellular Cardiology

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The calcium-activated protein phosphatase, calcineurin, lies at the intersection of protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic calcium, calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of calcineurin activity. Yet, it is widely recognized that excessive activation of calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a calcium activated enzyme function in the calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of calcineurin substrates relevant to cardiovascular health and the mechanisms calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of calcineurin signaling while avoiding the detrimental consequences of sustained calcineurin activity that can culminate in heart failure.

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“…Although many of these transcription factors are associated with development, interestingly, many are reactivated during pathological cardiac remodelling and hypertrophy 76, 77. Dyxin mRNA and protein levels exhibit a rapid biphasic (4 and 48 h) increase in the LV in response to pressure overload/biomechanical stress 78. This indicates that it is not only involved in the initial response to stress but also in the later hypertrophic remodelling stages.…”

Section: Sources Of Informationmentioning

confidence: 99%

The interactome of LIM domain proteins: The contributions of LIM domain proteins to heart failure and heart development

Pontén

Remedios

2012

Proteomics

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LIM domain proteins all contain at least one double zinc-finger motif. They belong to a large family and here we review those expressed mainly in mammalian hearts, but particularly in cardiomyocytes. These proteins contain between one and five LIM domains and usually these proteins contain other domains that have specific functions such as actin-binding, kinases and nuclear translocation motifs. While several recent reviews have summarised the importance of individual LIM domain proteins, this is the first review of its kind to cover all LIMs associated with the heart. Here we examine 33 LIM proteins (including three that bind to, but do not themselves contain, LIM domains) that are implicated in either the development of the heart, heart disorders and failure, or both. Our analysis is consistent with the view that cardiac LIM domain proteins form multiple extensive networks of multi-protein complexes within the myocardium. This multiplicity of binding partners probably protects the heart as it is challenged to maintain cardiac output, until the imbalance reaches a turning point that results in failure. We believe that the complexity of LIM interactions is properly described by the term LIM interactome.

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A novel p38 MAPK target dyxin is rapidly induced by mechanical load in the heart

Cited by 8 publications

References 26 publications

Characterization of the Regulatory Mechanisms of Activating Transcription Factor 3 by Hypertrophic Stimuli in Rat Cardiomyocytes

Characterization of the Regulatory Mechanisms of Activating Transcription Factor 3 by Hypertrophic Stimuli in Rat Cardiomyocytes

Calcineurin signaling in the heart: The importance of time and place

The interactome of LIM domain proteins: The contributions of LIM domain proteins to heart failure and heart development

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