RING Finger Protein RNF207, a Novel Regulator of Cardiac Excitation

Roder, Karim; Werdich, Andreas A.; Li, Weiyan; Liu, Man; Kim, Tae Yun; Darling, Louise E.O.; Moshal, Karni S.; Hwang, Jung Min; Lu, Yichun; Choi, Bum Rak; MacRae, Calum A.; Koren, Gideon

doi:10.1074/jbc.m114.592295

Cited by 41 publications

(35 citation statements)

References 64 publications

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“…Consistent with our results, the results of microarray analyses available from the NCBI public functional genomics data repository [21,61] showed that the mRNA level of Rnf207 is significantly reduced in NRCs treated with the pyridine activator of myocyte hypertrophy, which induces cardiac hypertrophy [62], and in mouse hearts treated with isoproterenol, which causes tachycardia-induced HF [63].…”

Section: Discussionsupporting

confidence: 91%

“…However, the precise molecular mechanism by which RNF207 affected the energy metabolism in isolated cardiomyocytes is not clear. Recent studies have shown that genetic variation in RNF207 is associated with prolongation of the QT interval [52,53] and that RNF207 knockdown in zebrafish embryos prolonged the action potential duration (APD) [21]. It was also reported that VDAC1 is the only identified protein mediating Ca 2+ transport in the outer mitochondrial membrane [54] and that Ca 2+ dynamics is important not only for APD [55,56] but also for the regulation of cellular energetic production [57][58][59].…”

Section: Discussionmentioning

confidence: 99%

“…is specifically expressed in the heart [20,21]. However, the detailed function of RNF207 in the heart has not been elucidated.…”

Section: The Really Interesting New Gene (Ring)-finger Domain Containmentioning

confidence: 99%

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The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

Mizushima

Takahashi

Watanabe

et al. 2016

Journal of Molecular and Cellular Cardiology

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A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction.Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure.Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure.3 Highlights l RNF207 is specifically expressed in the heart. l RNF207 enhances activity of the tricarboxylic acid cycle in cardiomyocytes.l RNF207 directly interacts with VDAC1 through its coiled-coil domain.l Heart failure significantly reduces the expression of RNF207 in mice.4

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

Mizushima

Takahashi

Watanabe

et al. 2016

Journal of Molecular and Cellular Cardiology

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“…With few exceptions, GWAS-identified loci that were not previously linked to cardiac electric function are yet untapped for gene identification and mechanistic insight. [182][183][184] In conducting functional studies on genes from GWAS loci (Figure 7), many considerations should be taken into account at the outset. Rather than a specific variant, GWAS illuminates a haplotype and any SNP on that haplotype that is in linkage disequilibrium with the lead-SNP from GWAS could in theory mediate the observed effect ( Figure 7B).…”

Section: Gwas On Ecg and Cardiac Structure And Function Parametersmentioning

confidence: 99%

Genetics of Sudden Cardiac Death

Bezzina

Lahrouchi

Priori

2015

Circulation Research

223

165

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Sudden cardiac death occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Genetic studies conducted during the past 20 years have markedly illuminated the genetic basis of the inherited cardiac disorders associated with sudden cardiac death. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels, and the cardiomyopathies, which have been attributed to mutations in genes encoding a broader category of proteins, including those of the sarcomere, the cytoskeleton, and desmosomes. We discuss the challenges currently faced in unraveling genetic factors that predispose to sudden cardiac death in the setting of sequela of coronary artery disease and present the genome-wide association studies conducted in recent years on electrocardiographic parameters, highlighting their potential in uncovering new biological insights into cardiac electric function. (Circ Res.

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“…9 In addition, RNF207 is also indirectly correlated to cardiac death via its interaction with QT interval prolongation, the main cause of arrhythmia. 10 RNF182, a cytoplasmic protein with low abundance, is predominantly expressed in the brain with amplified expression in postmortem Alzheimer's disease brain tissue, and its gene can be stimulated in cultured neurons subjected to cell death induced injuries. 11 Mammalian target of rapamycin (mTOR), as an atypical serine/threonine protein kinase, is the phosphoinositide 3-kinase (PI3K)-related kinase family and forms two kinds of different complexes named mTORC1 and mTORC2.…”

Section: Introductionmentioning

confidence: 99%

Activation of the mammalian target of rapamycin signaling pathway underlies a novel inhibitory role of ring finger protein 182 in ventricular remodeling after myocardial ischemia‐reperfusion injury

Wang

Wei

Gao

et al. 2018

J of Cellular Biochemistry

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Myocardial ischemia‐reperfusion injury (MIRI) is a major cause of cardiovascular disease, leading to mortality and disability associated with coronary occlusion worldwide. A correlation of mammalian target of rapamycin (mTOR)/nuclear factor‐kappa B (NF‐κB) signaling pathway has been observed with brain damage resulting from myocardial ischemia. Therefore, by establishing MIRI rat model, this study aimed to explore whether ring finger protein 182 (RNF182) regulates the mTOR signaling pathway affecting MIRI. Initially, MIRI rat model was successfully established, followed by either treatment of shRNF182 or phosphoesterase (PITE) (inhibitor of the mTOR signaling pathway). Then, the serum levels of superoxide dismutase (SOD), glutathione peroxidase (GSH‐Px) and malondialdehyde (MDA), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), and left ventricular end‐diastolic pressure (LVEDP) were determined, followed by detection of myocardial infarct sizes and myocardial cell apoptosis. Moreover, the levels of related genes/proteins were determined to further determine the mechanisms of RNF182 in MIRI. First, RNF182 was upregulated in MIRI. Another key observation of this study was that rats with shRNF182 presented with downregulated SOD, GSH‐Px, and MDA in serum, accompanied by decreased levels of LVEF, LVFS, LVSP, and LVEDP. In addition, both reduced myocardial infarct sizes and apoptosis of myocardial cells were observed after silencing RNF182. Furthermore, silencing of the RNF182 was observed to downregulate Bcl 2–associated X and cysteine proteinase 3 but upregulate mTOR, ribosome protein subunit 6 kinase 1, eukaryotic elongation factor 2, and B‐cell lymphoma‐2. Importantly, the effects of RNF182 silencing were reversed after PITE treatment. In conclusion, our study demonstrates that RNF182 silencing can prevent ventricular remodeling in rats after MIRI by activating the mTOR signaling pathway.

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RING Finger Protein RNF207, a Novel Regulator of Cardiac Excitation

Cited by 41 publications

References 64 publications

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

Genetics of Sudden Cardiac Death

Activation of the mammalian target of rapamycin signaling pathway underlies a novel inhibitory role of ring finger protein 182 in ventricular remodeling after myocardial ischemia‐reperfusion injury

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