Calcineurin Splicing Variant Calcineurin Aβ1 Improves Cardiac Function After Myocardial Infarction Without Inducing Hypertrophy

Felkin, Leanne E.; Narita, Takashi; Germack, Renée; Shintani, Yasunori; Takahashi, Kyoko; Sarathchandra, Padmini; López-Olañeta, Marina; Gómez-Salinero, Jesús M.; Suzuki, Ken; Barton, Paul J.R.; Rosenthal, Nadia; Lara‐Pezzi, Enrique

doi:10.1161/circulationaha.110.012211

Cited by 54 publications

(60 citation statements)

References 27 publications

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“…Similar to the C-terminal truncated CnA* proteins, the CnAβ1 variant is constitutively active. Remarkably, however, a cardiomyocyte-specific α MHC-Cn β 1 transgene does not provoke hypertrophy but exerts beneficial effects following myocardial infarction by promoting vascularization [34, 35]. How this is accomplished is not yet understood, however, interesting data is emerging that suggests CnAβ1 may be important for proper localization and signaling of mTORC2 complexes [34, 36].…”

Section: Calcineurin Structure and Regulationmentioning

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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Section: Calcineurin Structure and Regulationmentioning

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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“…We have previously shown that CnAβ1 regulates AKT phosphorylation (Felkin et al, 2011;López-Olañeta et al, 2014). To investigate whether CnAβ1 is controlling this pathway during mESC differentiation we knocked down CnAβ1 and induced the mESCs to differentiate to mesoderm.…”

Section: Cnaβ1 Regulates Mesoderm Specification Through Akt Gsk3 Andmentioning

confidence: 99%

“…In addition to known CnA interacting proteins like CnB (Felkin et al, 2011), we identified the interaction between CnAβ1 and Cog8, a protein enriched mainly in the external Golgi as well as other intracellular membranes that is involved in the interaction with the Cog and SNARE complexes (Laufman et al, 2013;Willett et al, 2013;Willett et al, 2014) (Table S4). To validate this interaction, we transfected cells with GFP-CnAβ1 chimeras and carried out immunoprecipitation and colocalization experiments.…”

Section: Cog8 Drives the Localization Of Cnaβ1 To The Golgi Apparatusmentioning

confidence: 99%

The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation

Gómez-Salinero

López-Olañeta

Ortiz-Sánchez

et al. 2016

Cell Chemical Biology

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Abstract:Embryonic stem cells (ESC) have the potential to generate all the cell lineages that will form the body. However, the molecular mechanisms underlying ESC differentiation and especially the role of alternative splicing in this process remain poorly understood. Here, we show that the alternative splicing regulator Mbnl1 promotes the generation of the atypical calcineurin Aβ variant CnAβ1 in mouse ESCs (mESC). CnAβ1 has a unique C-terminal domain that drives its localization mainly to Golgi apparatus by interacting with Cog8. CnAβ1 regulates the intracellular localization and activation of the mTORC2 complex. CnAβ1 knockdown results in delocalization of mTORC2 from the membrane to the cytoplasm, inactivation of the AKT/GSK3β/β-catenin signaling pathway and defective mesoderm specification. In summary, we unveil here the structural basis for the mechanism of action of CnAβ1 and its role in the differentiation of mESCs to the mesodermal lineage. Graphical Abstract Regulation of mesoderm specification by CnAβ1Gómez-Salinero et al. 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Regulation of mesoderm specification by CnAβ1Gómez-Salinero et al. knockdown results in delocalization of mTORC2 from the membrane to the cytoplasm, inactivation of the AKT/GSK3β/-catenin signaling pathway and defective mesoderm specification. In summary, we unveil here the structural basis for the mechanism of action of CnAβ1 and its role in the differentiation of mESCs to the mesodermal lineage. Page 2 of 36

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“…Cardiomyocyte hypertrophy can be estimated by measuring cell cross-sectional area after staining with wheat germ agglutinin [74]. Myocardial expression of HF markers such as brain natriuretic peptide (BNP), α-skeletal, actin, and, in some species, β-myosin heavy chain can be determined by qRT-PCR or by Western blot [75,76]. Expression of inflammation and fibrosis-related markers can also be quantified in this manner [77].…”

Section: Tissue Remodeling Fibrosis and Inflammationmentioning

confidence: 99%

Guidelines for Translational Research in Heart Failure

Lara‐Pezzi

Menasché

Trouvin

et al. 2015

J. of Cardiovasc. Trans. Res.

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Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropriate or incomplete preclinical studies. In these guidelines, we present a number of recommendations to enhance similarity between HF animal models and the human condition in order to reduce the chances of failure in subsequent clinical trials. We propose different approaches to address safety as well as efficacy of new therapeutic products. We also propose that good practice rules are followed from the outset so that the chances of eventual approval by regulatory agencies increase. We hope that these guidelines will help improve the translation of results from animal models to humans and thereby contribute to more successful clinical trials and development of new therapies for HF.

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Calcineurin Splicing Variant Calcineurin Aβ1 Improves Cardiac Function After Myocardial Infarction Without Inducing Hypertrophy

Cited by 54 publications

References 27 publications

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

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

The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation

Guidelines for Translational Research in Heart Failure

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