Translation of Myocyte Enhancer Factor-2 is induced by hypertrophic stimuli in cardiomyocytes through a Calcineurin-dependent pathway

Ye, Junmei; Cardona, Maria; Llovera, Marta; Comella, Joan X.; Sanchı́s, Daniel

doi:10.1016/j.yjmcc.2012.07.013

Cited by 19 publications

(9 citation statements)

References 45 publications

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“…As is known, Doppler parameters of LVDD may be abnormal in the absence of overt heart failure, but assessment of left ventricular diastolic properties cannot be relied on traditional Doppler parameters because such indexes as E/A, E deceleration time, and isovolumic relaxation time are mainly load dependent. 23,24 Meanwhile, we demonstrated that calcineurin and its pathway were involved in cardiac fibroblasts proliferation and transdifferentiation into myofibroblasts (data not published). 17,18 Olmesartan is a widely used angiotensin II type I receptor blocker for the treatment of hypertension, not only in terms of lowering blood pressure with renoprotective activity but also for inducing more prominent suppression of ventricular hypertrophy and fibrosis, leading to suppression of myocardial stiffening and improvement of relaxation as is evident in the present study and in others.…”

Section: Discussionmentioning

confidence: 99%

Olmesartan Attenuates Cardiac Hypertrophy and Improves Cardiac Diastolic Function in Spontaneously Hypertensive Rats Through Inhibition of Calcineurin Pathway

Zhou

et al. 2014

Journal of Cardiovascular Pharmacology

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Section: Discussionmentioning

confidence: 99%

Olmesartan Attenuates Cardiac Hypertrophy and Improves Cardiac Diastolic Function in Spontaneously Hypertensive Rats Through Inhibition of Calcineurin Pathway

Zhou

et al. 2014

Journal of Cardiovascular Pharmacology

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“…For instance, in response to hypertrophic agonists, there is a calcineurin-dependent increase in MEF2A and MEF2D protein levels due to an increase in the abundance of Polypyrimidine Tract Binding Protein (PTB) which then acts to increase translation of MEF2 proteins without altering transcript abundance [133]. It is not known whether PTB increases translation of other proteins with cardiovascular relevance.…”

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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“…Furthermore, we showed that a significant fraction of the transcript for MEF2D, which plays a relevant role in stressinduced gene expression in the adult (Kim et al, 2008), includes exon b in a PTB-inhibitable manner progressively after birth. Interestingly, we have recently found increased expression of MEF2A and MEF2D in myocytes treated with hypertrophic agonists and the hypertrophied adult heart (Ye et al, 2012). It can be hypothesized that, in the heart, exon b inclusion is important to define the activity of MEF2A and MEF2D when they are essential, but not in MEF2C, and that this splicing event is regulated by different mechanisms depending on the gene, with PTB being a relevant regulator of exon b splicing in Mef2a and Mef2d transcripts.…”

Section: Discussionmentioning

confidence: 99%

A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart

Ye¹,

Llorian²,

Cardona³

et al. 2013

Journal of Cell Science

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SummaryPolypyrimidine tract binding protein (PTB) regulates pre-mRNA splicing, having special relevance for determining gene expression in the differentiating muscle. We have previously shown that PTB protein abundance is progressively reduced during heart development without reduction of its own transcript. Simultaneous reduction of histone deacetylase (HDAC) expression prompted us to investigate the potential link between these events. HDAC5-deficient mice have reduced cardiac PTB protein abundance, and HDAC inhibition in myocytes causes a reduction in endogenous expression of cellular FLICE-like inhibitory protein (cFLIP) and caspase-dependent cleavage of PTB. In agreement with this, cardiac PTB expression is abnormally high in mice with cardiac-specific executioner caspase deficiency, and cFLIP overexpression prevents PTB cleavage in vitro. Caspase-dependent cleavage triggers further fragmentation of PTB, and these fragments accumulate in the presence of proteasome inhibitors. Experimental modification of the above processes in vivo and in vitro results in coherent changes in the alternative splicing of genes encoding tropomyosin-1 (TPM1), tropomyosin-2 (TPM2) and myocyte enhancer factor-2 (MEF2). Thus, we report a pathway connecting HDAC, cFLIP and caspases regulating the progressive disappearance of PTB, which enables the expression of the adult variants of proteins involved in the regulation of contraction and transcription during cardiac muscle development.

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Translation of Myocyte Enhancer Factor-2 is induced by hypertrophic stimuli in cardiomyocytes through a Calcineurin-dependent pathway

Cited by 19 publications

References 45 publications

Olmesartan Attenuates Cardiac Hypertrophy and Improves Cardiac Diastolic Function in Spontaneously Hypertensive Rats Through Inhibition of Calcineurin Pathway

Olmesartan Attenuates Cardiac Hypertrophy and Improves Cardiac Diastolic Function in Spontaneously Hypertensive Rats Through Inhibition of Calcineurin Pathway

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

A pathway involving HDAC5, cFLIP and caspases regulates expression of the splicing regulator polypyrimidine tract binding protein in the heart

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