Inhibition of nuclear import of calcineurin prevents myocardial hypertrophy

Hallhuber, Matthias; Burkard, Natalie; Wu, Ruiheng; Buch, Mamta H.; Neyses, Ludwig; Schuh, Kai; Ritter, Oliver

doi:10.1016/j.yjmcc.2006.03.073

Cited by 12 publications

(14 citation statements)

References 18 publications

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“…The important role of ET-1-stimulated IICR in the nucleus for the activation of the CnA/NFAT pathway was further substantiated by the decrease in ET-1-induced ANF expression observed in myocytes treated with a cell-permeant peptide inhibitor of CnA nuclear translocation (Hallhuber et al, 2006) ( Figure 3C). Together, these data show that ET-1 induces hypertrophy by causing InsP 3 -stimulated increases in nuclear Ca 2+ , which activates the CnA/NFAT pathway.…”

Section: Et-1 and Insp 3 Ester Stimulate Increases In Nuclear Ca 2+mentioning

confidence: 72%

Endothelin-1-Stimulated InsP3-Induced Ca2+ Release Is a Nexus for Hypertrophic Signaling in Cardiac Myocytes

et al. 2009

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Ca(2+) elevations are fundamental to cardiac physiology-stimulating contraction and regulating the gene transcription that underlies hypertrophy. How Ca(2+) specifically controls gene transcription on the background of the rhythmic Ca(2+) increases required for contraction is not fully understood. Here we identify a hypertrophy-signaling module in cardiac myocytes that explains how Ca(2+) discretely regulates myocyte hypertrophy and contraction. We show that endothelin-1 (ET-1) stimulates InsP(3)-induced Ca(2+) release (IICR) from perinuclear InsP(3)Rs, causing an elevation in nuclear Ca(2+). Significantly, we show that IICR, but not global Ca(2+) elevations associated with myocyte contraction, couple to the calcineurin (CnA)/NFAT pathway to induce hypertrophy. Moreover, we found that activation of the CnA/NFAT pathway and hypertrophy by isoproterenol and BayK8644, which enhance global Ca(2+) fluxes, was also dependent on IICR and nuclear Ca(2+) elevations. The activation of IICR by these activity-enhancing mediators was explained by their ability to stimulate secretion of autocrine/paracrine ET-1.

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Section: Et-1 and Insp 3 Ester Stimulate Increases In Nuclear Ca 2+mentioning

confidence: 72%

Endothelin-1-Stimulated InsP3-Induced Ca2+ Release Is a Nexus for Hypertrophic Signaling in Cardiac Myocytes

et al. 2009

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“…The presence of calcineurin in the nucleus is important for full NF-AT (nuclear factor of activated T cells) transcriptional activity. When the nuclear entry of calcineurin is blocked, development of myocardial hypertrophy can be prevented (40). Similarly, we hypothesize that an agent that binds and block the hairpin loops of myotrophin or specific residues like Glu 33 would attenuate myotrophin-induced cardiomyocyte hypertrophy.…”

Section: Discussionmentioning

confidence: 93%

“…To date, all these data suggest that the hairpin loop of myotrophin is involved in activation of NF-B; once activated by myotrophin, NF-B-p65 may function as a nuclear transport factor for myotrophin translocation. In this capacity, p65 could play a role comparable with that of importin ␤-1, which is responsible for nuclear translocation of calcineurin (40). Down-regulation of NF-B-p65 nuclear translocation in the E33A mutant leading to attenuation of myocyte growth is similar to attenuation of angiotensin II-induced cardiomyocyte hypertrophy by down-regulation of NF-B-p65 nuclear import driven by focal adhesion kinase-related nonkinase (41).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Co-translocation of Myotrophin and p65 Stimulates Myocyte Growth

Das

Gupta

Vasanji

et al. 2008

Journal of Biological Chemistry

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Myotrophin, a 12-kDa ankyrin repeat protein, stimulates protein synthesis and cardiomyocyte growth to initiate cardiac hypertrophy by activating the NF-B signaling cascade. We found that, after internalization into myocytes, myotrophin cotranslocates into the nucleus with p65 to stimulate myocyte growth. We used structure-based mutations on the hairpin loops of myotrophin to determine the effect of the loops on myotrophin and p65 localization, induction of protein synthesis, and cardiac hypertrophy. Loop mutants, most prominently glutamic acid 33 3 alanine (E33A), stimulated protein synthesis much less than wild type. Myotrophin-E33A internalized into myocytes but did not translocate into the nucleus and failed to promote nuclear translocation of p65. In addition, two cardiac hypertrophy marker genes, atrial natriuretic factor and ␤-myosin heavy chain, were not up-regulated in E33A-treated cells. Myotrophin-induced myocyte growth and initiation of hypertrophy thus require nuclear co-translocation of myotrophin and p65, in a manner that depends crucially on the myotrophin hairpin loops.Myotrophin, a 12-kDa protein, is the smallest known ankyrin (ANK) 2 repeat protein (1) and contains four ANK repeats (2, 3). Myotrophin, also known as V-1 protein, was identified in spontaneously hypertensive rat hearts, cardiomyopathic human hearts (4), and neonatal rat cerebella (5). Myotrophin expression is ubiquitous in mammalian tissues (6). It is known to participate in the catecholamine synthesis signaling pathway (7), in regulation of actin polymerization (8), and in regulation of capping and uncapping by actin capping protein at the barbed ends of actin filaments (9). Myotrophin plays an important role in stimulation of cardiac myocyte growth and cardiac hypertrophy (4, 10). Sil et al. (11) reported an increase in myotrophin levels in human cardiomyopathic heart compared with normal heart. Overexpression of myotrophin in transgenic mice initiates cardiac hypertrophy that progresses toward heart failure (12, 13). Significantly, an increase in myotrophin level in blood plasma is observed after acute myocardial infarction (14) and in patients with heart failure (15). These data have established myotrophin as an initiator of cardiac hypertrophy and eventual heart failure.Myotrophin has been shown to interact with NF-B proteins (6, 16), and myotrophin-induced myocyte growth appears to be mediated through activation of the NF-B pathway (10), although the details of these interactions are poorly characterized. Knuefermann et al. (16) showed that myotrophin physically associates with p65 and prevents the reassociation of the p65-p50 heterodimer, resulting in activation of the NF-B pathway. Separate studies have established the involvement of NF-B signaling in cardiac hypertrophy and dilated cardiomyopathy (17-19) and the importance of NF-B activation in the pathogenesis of cardiac remodeling and heart failure (20 -22). Recently, Gupta et al. (13) showed that progression of cardiac hypertrophy to heart failure is associated with...

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“…The current study has generated new insights into the nuclear transport mechanisms of GATA-4 and the residues involved in its DNA binding activity and may provide useful information in the development of novel cardiac-related therapies. Indeed, recently, a peptide that competes with the NLS of calcineurin and hence inhibits calcineurin nuclear import was successfully developed for the prevention of cardiac hypertrophy in vitro (56). Considering that GATA-4 overexpression is sufficient to cause myocardial hypertrophy, understanding the nuclear transport of this transcription factor may potentially lead to novel therapeutic strategies for the prevention of cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Signals and Mechanisms Mediating Nuclear Trafficking of GATA-4

Philips¹,

Kwok²,

Chong

2007

Journal of Biological Chemistry

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Nucleocytoplasmic transport of GATA-4 is important in maintaining and regulating normal cardiogenesis and heart function. This report investigates the detailed mechanisms of GATA-4 nuclear transport. We characterized a nonclassical nuclear localization signal between amino acids 270 and 324 that actively transports GATA-4 into the nucleus of both HeLa cells and cardiac myocytes. Fine mapping studies revealed four crucial arginine residues within this region that mediate active transport predominately through the nonclassical pathway via interaction with importin ␤. These four residues were also essential for the DNA binding activity of GATA-4 and transcriptional activation of cardiac-specific genes. Interestingly, mutation of these residues not only inhibited DNA binding and gene transcription but also resulted in a preferential accumulation of the GATA-4 protein in distinct subnuclear speckles. A cardiac myocyte-specific, chromosome maintenance region 1-dependent nuclear export signal consisting of three essential leucine residues was also identified. The current study provides detailed information on the nuclear shuttling pathways of GATA-4 that represents an additional mechanism of gene regulation.

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Inhibition of nuclear import of calcineurin prevents myocardial hypertrophy

Cited by 12 publications

References 18 publications

Endothelin-1-Stimulated InsP3-Induced Ca2+ Release Is a Nexus for Hypertrophic Signaling in Cardiac Myocytes

Endothelin-1-Stimulated InsP3-Induced Ca2+ Release Is a Nexus for Hypertrophic Signaling in Cardiac Myocytes

Nuclear Co-translocation of Myotrophin and p65 Stimulates Myocyte Growth

Analysis of the Signals and Mechanisms Mediating Nuclear Trafficking of GATA-4

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