Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex

Li, Huihua; Kedar, Vishram; Zhang, Chunlian; McDonough, Holly; Arya, Ranjana; Wang, Dazhi; Patterson, Cam

doi:10.1172/jci200422220

Cited by 352 publications

(374 citation statements)

References 54 publications

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“…Previous studies showed FoxO1 and FoxO3 can promote expression of the atrophy-associated ubiquitin ligase gene atrogin-1, and Atrogin-1 can also activate FoxO1 function in cardiomyocyte cell cycle control (26,33,59). Similarly in skeletal muscle, FoxO3 induces both atrophy and autophagy, leading to decreased cell size through direct regulation of atrophy and autophagy-associated genes (29,30).…”

Section: Discussionmentioning

confidence: 99%

FoxO Transcription Factors Promote Autophagy in Cardiomyocytes

Sengupta

Molkentin

Yutzey

2009

Journal of Biological Chemistry

384

304

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Section: Discussionmentioning

confidence: 99%

FoxO Transcription Factors Promote Autophagy in Cardiomyocytes

Sengupta

Molkentin

Yutzey

2009

Journal of Biological Chemistry

384

304

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“…Interpretation of these studies is problematic, however, because cyclosporin A mediates calcineurin-independent effects, and MCIP has dual effects on calcineurin activity (37)(38)(39). In a recent study (40), the F-box adapter protein atrogin-1 was identified as a unique binding partner of calcineurin and ␣-actinin at the Z-disk. In the face of hemodynamic stress, atrogin-1 promotes ubiquitin-dependent degradation of calcineurin, resulting in a reduced hypertrophic response (less cardiomyocyte thickening), enhanced cardiac dilation, and enhanced ventricular dysfunction (40).…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study (40), the F-box adapter protein atrogin-1 was identified as a unique binding partner of calcineurin and ␣-actinin at the Z-disk. In the face of hemodynamic stress, atrogin-1 promotes ubiquitin-dependent degradation of calcineurin, resulting in a reduced hypertrophic response (less cardiomyocyte thickening), enhanced cardiac dilation, and enhanced ventricular dysfunction (40). These data are very much reminiscent of our findings that impaired MLP-calcineurin signaling at the Z-disk is associated with blunted transverse myocyte growth, more pronounced ventricular dilation, and contractile dysfunction (i.e., adverse remodeling).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc

Heineke

Ruetten

Willenbockel

et al. 2005

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

142

138

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Adverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause for heart failure. Molecular modifiers of the remodeling process remain poorly defined. Patients with heart failure after MI have reduced LV expression levels of muscle LIM protein (MLP), a component of the sarcomeric Z-disk that is involved in the integration of stress signals in cardiomyocytes. By using heterozygous MLP mutant (MLP ؉/؊ ) mice, we explored the role of MLP in post-MI remodeling. LV dimensions and function were similar in sham-operated WT and MLP ؉/؊ mice. After MI, however, MLP ؉/؊ mice displayed more pronounced LV dilatation and systolic dysfunction and decreased survival compared with WT mice, indicating that reduced MLP levels predispose to adverse LV remodeling. LV dilatation in MLP ؉/؊ mice was associated with reduced thickening but enhanced elongation of cardiomyocytes. Activation of the stress-responsive, prohypertrophic calcineurinnuclear factor of activated T-cells (NFAT) signaling pathway was reduced in MLP ؉/؊ mice after MI, as shown by a blunted transcriptional activation of NFAT in cardiomyocytes isolated from MLP ؉/؊ ͞NFAT-luciferase reporter gene transgenic mice. Calcineurin was colocalized with MLP at the Z-disk in WT mice but was displaced from the Z-disk in MLP ؉/؊ mice, indicating that MLP is essential for calcineurin anchorage to the Z-disk. In vitro assays in cardiomyocytes with down-regulated MLP confirmed that MLP is required for stress-induced calcineurin-NFAT activation. Our study reveals a link between the stress sensor MLP and the calcineurin-NFAT pathway at the sarcomeric Z-disk in cardiomyocytes and indicates that reduced MLP-calcineurin signaling predisposes to adverse remodeling after MI.heart failure ͉ stress signaling C hronic heart failure is a worldwide epidemic. Recently, a fundamental shift in the underlying etiology of heart failure has occurred, in which the most common cause of heart failure is no longer hypertension or valvular disease, but myocardial infarction (MI) (1). MI induces profound alterations of left ventricular (LV) architecture with scar formation, ventricular dilatation, and hypertrophy of the noninfarcted (remote) myocardium (2). Biomechanical stress and humoral growth factors are important mediators of this remodeling process (3, 4). At the level of the single cardiomyocyte, post-MI LV remodeling is characterized by increases in cell diameter and cell length and alterations in gene expression levels (5-7).The Z-disk is a multiprotein complex located at the interface of the cytoskeleton, the contractile apparatus, and the sarcolemma in cardiomyocytes (8). Muscle LIM protein (MLP), which is tethered to the Z-disk via its interacting partners, ␣-actinin and telethonin, has been proposed to be an essential part of the mechanical stretch sensor machinery (9) and to be involved in the transmission of humoral growth signals in cardiomyocytes (10). Intriguingly, myocardial MLP levels are reduced by Ϸ50% in patients with heart failure after MI (11). However, ...

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“…Quantitative PCR primers for ANF, brain natriuretic factor, b-myosin heavy chain and GAPDH were as described earlier. 23 …”

Section: Real-time Quantitative Pcr Analysismentioning

confidence: 99%

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

et al. 2010

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GATA6 is a member of the GATA family of transcription factors, and its expression and functions overlap with those of GATA4 during heart development. Mutations in GATA4 have been related to human congenital heart diseases (CHDs) in several studies, whereas mutations in GATA6 have only recently been reported in patients with persistent truncus arteriosus. Animal experiments have revealed critical roles for GATA6 in the development of the myocardium and cardiac morphogenesis, thereby highlighting the potential involvement of GATA6 defects in the pathogenesis of CHDs. Here, we screened the GATA6 in 270 individuals with sporadic CHDs by direct sequencing. After identification of the mutation, a luciferase reporter assay and real-time quantitative polymerase chain reaction were performed to detect functional changes in the mutant transcription factor. The same heterozygous missense mutation (Ser184Asn) was identified in three patients, including one with tetralogy of Fallot and two with atrial septal defects. This mutation was not found in 500 unrelated ethnically matched healthy subjects. Direct sequencing of this region in the parents of these three patients revealed the same mutation in one of the parents for each patient, and one of the parent carriers presented with a bicuspid aortic valve. Biological analysis revealed clearly decreased transcriptional activity of GATA6 Ser184Asn in vitro. All these data suggest that GATA6 Ser184Asn is a novel mutation associated with CHDs and has an important role in disease pathogenesis.

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Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex

Cited by 352 publications

References 54 publications

FoxO Transcription Factors Promote Autophagy in Cardiomyocytes

FoxO Transcription Factors Promote Autophagy in Cardiomyocytes

Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc

A novel GATA6 mutation in patients with tetralogy of Fallot or atrial septal defect

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