Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Oakley, Robert H.; Ren, Rongqin; Cruz‐Topete, Diana; Bird, Gary S.; Myers, Page; Boyle, Michael C.; Schneider, Michael; Willis, Monte S.; Cidlowski, John A.

doi:10.1073/pnas.1302546110

Cited by 110 publications

(125 citation statements)

References 22 publications

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“…Global gene expression analysis of the hearts of these mice revealed significant dysregulation of several gene networks associated with cardiomyocyte homeostasis and function. Among these genes, we observed two members of the Krüppel-like factor (KLF) family of transcriptional regulators, Klf15 and Klf13 (14).…”

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confidence: 99%

“…Upon ligand binding, glucocorticoid receptor translocates to the nucleus to regulate the expression of thousands of genes through direct DNA binding, by interacting with other transcription factors, and by regulation of RNA turnover (4 -6). Glucocorticoid receptors are highly expressed in heart cardiomyocytes, fibroblasts, and endothelial cells (7)(8)(9)(10)(11)(12), and several direct actions of glucocorticoids in the heart have been described in vivo (13,14). For example, Rog-Zielinska et al (13) recently demonstrated that glucocorticoid signaling in cardiomyocytes is necessary for heart maturation during development.…”

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confidence: 99%

“…For example, Rog-Zielinska et al (13) recently demonstrated that glucocorticoid signaling in cardiomyocytes is necessary for heart maturation during development. Mice lacking glucocorticoid receptors in cardiomyocytes develop spontaneous cardiac hypertrophy, left ventricular systolic dysfunction, heart failure, and death (14). Global gene expression analysis of the hearts of these mice revealed significant dysregulation of several gene networks associated with cardiomyocyte homeostasis and function.…”

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confidence: 99%

“…They have been implicated in the regulation of an array of cellular processes (16), including cardiac biology (14,17,18). KLF13 and KLF15, in particular, have both been suggested to play roles in the heart (14,17,19), and KLF15 expression is directly induced by glucocorticoids (18,20). KLF15 is known to be a transcriptional repressor of pathological cardiac hypertrophy (14,17), and as a regulator of cardiac lipid metabolism (18).…”

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confidence: 99%

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Krüppel-like Factor 13 Is a Major Mediator of Glucocorticoid Receptor Signaling in Cardiomyocytes and Protects These Cells from DNA Damage and Death

Cruz‐Topete¹,

et al. 2016

Journal of Biological Chemistry

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Glucocorticoid receptor (GR) signaling has recently been shown to play a direct role in the regulation of cardiomyocyte function. In this study, we investigated the potential role of KLF13 as a downstream effector of GR action utilizing both in vivo and in vitro approaches. Our data show that KLF13 mRNA and protein levels are significantly diminished in the hearts of mice lacking GR in cardiomyocytes. Glucocorticoid administration up-regulated Klf13 mRNA in the mouse heart, in isolated primary cardiomyocytes, and in immortal cardiomyocyte cell lines. Glucocorticoid Klf13 gene expression was abolished by treatment with a GR antagonist (RU486) or by knockdown of GR in cardiomyocytes. Moreover, glucocorticoid induction of Klf13 mRNA was resistant to de novo protein synthesis inhibition, demonstrating that Klf13 is a direct glucocorticoid receptor gene target. A glucocorticoid responsive element (GRE) was identified in the Klf13 gene and its function was verified by chromatin immunoprecipitation in HL-1 cells and mouse hearts. Functional studies showed that GR regulation of Klf13 is critical to protect cardiomyocytes from DNA damage and cell death induced by cobalt(II) chloride hexahydrate (CoCl 2 ⅐6H 2 O) and the antineoplastic drug doxorubicin. These results established a novel role for GR and KLF13 signaling in adult cardiomyocytes with potential clinical implications for the prevention of cardiotoxicity induced heart failure.

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Krüppel-like Factor 13 Is a Major Mediator of Glucocorticoid Receptor Signaling in Cardiomyocytes and Protects These Cells from DNA Damage and Death

Cruz‐Topete¹,

et al. 2016

Journal of Biological Chemistry

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“…In the GR deficient hearts, the expression of ryanodine receptor 2 (RyR2) is reportedly suppressed in the cardiomyocytes of GR deficiency. RyR2 is involved in abnormal calcium handling in cardiac hypertrophy and heart failure [15]. To facilitate coordinated Ca-induced Ca release, groups of RyR2 are localized in discrete areas in the sarcoplasmic reticulum (SR) membrane directly adjacent to L-type Ca channels within the Ttubules of the sarcolemma [16].…”

Section: Discussionmentioning

confidence: 99%

Prolonged QT Intervals in Isolated ACTH Deficiency: Case Report and Mini Review of Literature

Suzuki¹,

Hayashi

Asano³

et al. 2016

J Steroids Horm Sci

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Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare disorder, characterized by secondary adrenal insufficiency. We experienced a case of isolated ACTH deficiency presented with prolonged QT intervals which was helpful in diagnosis. Hereby we report our case and review the previous cases. We describe a 77 year-old female whose major complaints were general malaise, anorexia, and depression. On admission, QT intervals of ECG were prolonged. Endocrine tests indicated that she was suffering from isolated ACTH deficiency. After hydrocortisone replacement therapy was started, QT intervals were shortened and all of her complaints were resolved. There are only six reports about isolated ACTH deficiency associated with prolonged QT intervals until now. Prolongation of QT intervals is known to be a risk factor for cardiovascular events such as ventricular fibrillation, but interestingly prolonged QT intervals associated with isolated ACTH deficiency infrequently cause lethal arrhythmia. The initial symptoms of adrenal deficiency in elderly patients are obscure and adrenal deficiency is often misdiagnosed as unidentified clinical syndrome. It is important to consider isolated ACTH deficiency when recognizing unexplained prolonged QT intervals.

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Posttranslational modifications of lysine and evolving role in heart pathologies—Recent developments

Št́astná

Eyk

2015

Proteomics

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The alteration in proteome composition induced by environmental changes and various pathologies is accompanied by the modifications of proteins by specific cotranslational and PTMs. The type and site stoichiometry of PTMs can affect protein functions, alter cell signaling, and can have acute and chronic effects. The particular interest is drawn to those amino acid residues that can undergo several different PTMs. We hypothesize that these selected amino acid residues are biologically rare and act within the cell as molecular switches. There are, at least, 12 various lysine modifications currently known, several of them have been shown to be competitive and they influence the ability of a particular lysine to be modified by a different PTM. In this review, we discuss the PTMs that occur on lysine, specifically neddylation and sumoylation, and the proteomic approaches that can be applied for the identification and quantification of these PTMs. Of interest are the emerging roles for these modifications in heart disease and what can be inferred from work in other cell types and organs.

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Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Cited by 110 publications

References 22 publications

Krüppel-like Factor 13 Is a Major Mediator of Glucocorticoid Receptor Signaling in Cardiomyocytes and Protects These Cells from DNA Damage and Death

Krüppel-like Factor 13 Is a Major Mediator of Glucocorticoid Receptor Signaling in Cardiomyocytes and Protects These Cells from DNA Damage and Death

Prolonged QT Intervals in Isolated ACTH Deficiency: Case Report and Mini Review of Literature

Posttranslational modifications of lysine and evolving role in heart pathologies—Recent developments

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