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

Li, Hui Hua; Kedar, Vishram; Zhang, Chunlian; McDonough, Holly; Arya, Ranjana; Wang, Da Zhi; Patterson, Cam

doi:10.1172/jci22220

Cited by 169 publications

(153 citation statements)

References 55 publications

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“…We have also demonstrated the treatment potential of Fbxo32 through Berberine, which is consistent with a study using a cardiomyocyte-specific Fbxo32-overexpression mouse model to show resistance against TAC-induced hypertrophy through PP2B downregulation. 11 However, we do not exclude the possibility that Berberine activates other antihypertrophic pathways as previous studies have indicated upregulation of autophagy. 10,41 Together, this study highlights the novel components, Smad3 and Fbxo32, as well as Pak1 itself as attractive drug targets for future studies on therapeutic treatment in halting or reversing the progression of hypertrophy.…”

Section: Discussionmentioning

confidence: 71%

“…12,13 In cardiomyocytes, Fbxo32 was shown to colocalize with calcineurin (PP2B); furthermore, overexpression of Fbxo32 reduced PP2B levels resulting in cytoplasmic retention of the transcription factor, nuclear factor of activated T cells (NFAT), which in turn prevents its prohypertrophic effects. 11,[14][15][16] P21-activated kinase 1 (Pak1) has been discovered as an important serine/threonine kinase with crucial functions in the heart. [17][18][19] It belongs to the group I Pak family and is activated by GTP-bound Cdc42/Rac1 GTPases.…”

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confidence: 99%

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Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Tsui

Wang

et al. 2015

Hypertension

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Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure. Many signal transduction cascades are demonstrated to dictate the induction and progression of pathological hypertrophy; however, our understanding in regulatory mechanisms responsible for the suppression of hypertrophy remains limited. In this study, we showed that exacerbated hypertrophy induced by pressure overload in cardiac-deleted Pak1 mice was attributable to a failure to upregulate the antihypertrophic E3 ligase, Fbxo32, responsible for targeting proteins for the ubiquitin-degradation pathway. Under pressure overload, cardiac overexpression of constitutively active Pak1 mice manifested strong resilience against pathological hypertrophic remodeling. Mechanistic studies demonstrated that subsequent to Pak1 activation, the binding of Smad3 on a critical singular AGAC -286 -binding site on the FBXO32 promoter was crucial for its transcriptional regulation. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling and improved cardiac performance in cardiac-deficient Pak1 mice under pressure overload. Our findings discover Smad3 and Fbxo32 as novel downstream components of the Pak1-dependent signaling pathway for the suppression of hypertrophy. This discovery opens a new venue for opportunities to identify novel targets for the management of cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Tsui

Wang

et al. 2015

Hypertension

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“…Numerous studies have demonstrated that E3 ubiquitin ligases play important roles in protecting myocardial infarction, cardiac hypertrophy and fibrosis [15,16,18,24,25,27,28,29]. CHIP has been identified as an E3 ubiquitin ligase/chaperone protein that is highly expressed in the various tissues and cell types [26].…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis was performed as described [24,25]. Fifty µg protein lysates were separated by 10% SDS-PAGE and then transferred to nitrocellulose membranes (Bio-Rad), the membranes were incubated with primary antibody against p53 (1:500), CHIP (1:500; Santa Cruz Biotechnology, Santa Cruz, CA) and β-actin (Cell Signaling Technology, Beverly, MA, 1:3000) at 4°C overnight.…”

Section: Methodsmentioning

confidence: 99%

CHIP Enhances Angiogenesis and Restores Cardiac Function After Infarction in Transgenic Mice

Zhang²,

Wang³

et al. 2013

Cell Physiol Biochem

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Background: Carboxyl terminus of Hsp70-interacting protein (CHIP) is a chaperone/ubiquitin ligase that plays an important role in stress-induced apoptosis. However, the effect of CHIP on angiogenesis, cardiac function and survival 4 weeks after myocardial infarction (MI) remain to be explored. Methods: Wild-type (WT) and transgenic mice (TG) with cardiac-specific overexpression of CHIP were used for coronary artery ligation. The cardiac function, cardiomyocyte apoptosis, inflammation and angiogenesis were examined by echocardiography, histological analysis, real-time PCR and Western blot analysis. Results: At 4 weeks of after coronary artery ligation, echocardiography demonstrated that cardiac remodeling and dysfunction were prevented in TG mice compared with WT mice. The infarct size, cardiomyocyte apoptosis and inflammation were significantly reduced in TG mice than in WT mice. The survival rate after MI in TG mice was higher than that of WT mice. Furthermore, the levels of p53 protein was markedly decreased, but the expression of HIF-1α and VEGF, and the formation of capillary and arteriole after MI were significantly enhanced in TG mice compared with WT mice. Conclusion: We report the first in vivo evidence that CHIP enhances angiogenesis, inhibits inflammation, restores cardiac function, and improves survival at 4 weeks after MI. The present study expands on previous results and defines a novel mechanism. Thus, increased CHIP level may provide a novel therapeutic approach for left ventricular dysfunction after MI.

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“…Neonatal rat cardiomyocytes were isolated by enzymatic disassociation of 1-day-old SD rats as described previously [20]. Recombinant adenoviruses expressing green fluorescent protein (Ad-GFP) or Nrdp1 (Ad-Nrdp1) driven by the cytomegalovirus promoter were generated by the use of the Ad-Easy system (MP Biomedicals Inc.) [20].…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Effects of E3 Ligase Nrdp1 on Hypertrophy in Neonatal Rat Cardiomyocytes by Microarray and Integrated Gene Network Analysis

Zhang

Su²,

Zhang³

2016

Cardiology

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Objective: Neuregulin receptor degradation protein-1 (Nrdp1) is a novel E3 ubiquitin ligase, and we have previously shown that overexpression of Nrdp1 increased cardiomyocyte injury. However, the role of Nrdp1 in myocardial hypertrophy is unclear. In the present study, we clarified the molecular mechanisms of angiotensin II (Ang II)-induced cardiomyocyte hypertrophy regulated by Nrdp1 based on genome-wide transcriptional analysis. Methods: Neonatal rat cardiomyocytes were infected with adenoviruses containing green fluorescent protein (Ad-GFP) or wild-type Nrdp1 (Ad-Nrdp1), and then treated with Ang II for 36 h. Detection of differentially expressed genes was achieved with an Affymetrix Rat Gene 2.0 Array and Cluster and Java TreeView software. Results and Conclusion: Microarray data analysis demonstrated that Nrdp1 overexpression affected the expression of 12,140 mRNA genes in Ang II-induced cardiomyocyte hypertrophy, including the upregulation of 12,044 and the downregulation of 96. Gene ontology and globe signal transduction network analysis showed that Nrdp1 affected the expression of many genes related to stimulus response, the cell receptor pathway, and cell growth. Pathway network analysis identified myocardial metabolism, DNA replication, and the cell cycle as the most important pathways targeted by Nrdp1. lncRNA-mRNA coexpression network analysis showed that two core lncRNAs, NONRATT057160 and NONRATT054243, were involved in cardiomyotrophy regulated by Nrdp1 in cardiomyocytes. Taken together, these data provide compelling clues for further exploration of the function of Nrdp1 in heart disease.

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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 169 publications

References 55 publications

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32

CHIP Enhances Angiogenesis and Restores Cardiac Function After Infarction in Transgenic Mice

Transcriptional Effects of E3 Ligase Nrdp1 on Hypertrophy in Neonatal Rat Cardiomyocytes by Microarray and Integrated Gene Network Analysis

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