DNA Damage Response Mediates Pressure Overload–Induced Cardiomyocyte Hypertrophy

Nakada, Yuji; Nguyen, Ngoc Uyen Nhi; Xiao, Feng; Savla, Jainy; Lam, Nicholas T.; Abdisalaam, Salim; Bhattacharya, Souparno; Mukherjee, Shibani; Asaithamby, Aroumougame; Gillette, Thomas G.; Hill, Joseph A.; Sadek, Hesham A.

doi:10.1161/circulationaha.118.034822

Cited by 38 publications

(33 citation statements)

References 5 publications

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“…Future experiments will be required to address whether this interaction also occurs in vivo . Moreover, the study shows that ATM activation and activity is not exclusively dependent on HMGB1 because a synergistic cardioprotective effect is observed in HMGB1-Tg animals treated with both Ang II and the ATM inhibitor KU55933, confirming recently published evidence that pharmacologic inhibition of ATM prevents detrimental cardiac remodeling (9).…”

supporting

confidence: 84%

“…DDR is observed also in post-mitotic cells such as cardiomyocytes, and its prolonged activation promotes apoptosis and detrimental cardiac remodeling after myocardial infarction 6, 7. Persistent DDR plays a role in the pathogenesis of HF as well, and various types of damage, including oxidative DNA damage and DNA single- and double-strand breaks, have been found in cardiomyocytes of patients with end-stage HF and in the hearts of mice with cardiac hypertrophy induced by transverse aortic constriction or Ang II infusion 7, 8, 9. Genetic reduction of ATM attenuates left ventricular dysfunction and improves mortality in mice that underwent transverse aortic constriction by reducing nuclear factor-κB–mediated cardiac inflammation (8).…”

mentioning

confidence: 99%

“…Genetic reduction of ATM attenuates left ventricular dysfunction and improves mortality in mice that underwent transverse aortic constriction by reducing nuclear factor-κB–mediated cardiac inflammation (8). Cardiomyocyte-specific genetic ablation or pharmacological inhibition of ATM reduces cardiac hypertrophy by preventing calcineurin expression and eukaryotic translation initiation factor 4E–binding protein 1 phosphorylation (9).…”

mentioning

confidence: 99%

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Nuclear Hmgb1

Raucci

Capogrossi

2019

JACC: Basic to Translational Science

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supporting

confidence: 84%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Nuclear Hmgb1

Raucci

Capogrossi

2019

JACC: Basic to Translational Science

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“…Interestingly, KEGG pathway analysis of this signature demonstrated changes in the p53 signaling pathway, DNA replication, homologous recombination and Fanconi anemia (Supplemental Figure 7). Recent studies point towards the importance of p53 and proteins involved in DNA metabolism for the development of cardiac hypertrophy (Das et al, 2010; Nakada et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes

Rozwadowska

Clark

et al. 2019

Stem Cell Research

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Friedreich’s ataxia is caused by large homozygous, intronic expansions of GAA repeats in the frataxin (FXN) gene, resulting in severe downregulation of its expression. Pathogenic repeats are located in intron one, hence patients express unaffected FXN protein, albeit in low quantities. Although FRDA symptoms typically afflict the nervous system, hypertrophic cardiomyopathy is the predominant cause of death. Our studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease.

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“…DNA damage is linked to several human diseases, including cancer, neurodegeneration, aging and CVDs ( Madabhushi et al, 2014 ; Ou and Schumacher, 2018 ; Nakada et al, 2019 ; Reisländer et al, 2020 ). In the early stage of DNA damage, SIRT6 recruited SNF2H (an ATP-dependent chromatin remodeling) to DNA double-stranded breakpoint (DSB), to prevent genomic instability via local deacetylation of H3K56, and effectively recruited repair factors 53BP1, BRCA1, and RPA for damage repair ( Toiber et al, 2013 ).…”

Section: Sirt6 and Senescencementioning

confidence: 99%

SIRT6 in Senescence and Aging-Related Cardiovascular Diseases

Liu

et al. 2021

Front. Cell Dev. Biol.

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SIRT6 belongs to the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Its function is similar to the Silent Information Regulator 2 (SIR2), which prolongs lifespan and regulates genomic stability, telomere integrity, transcription, and DNA repair. It has been demonstrated that increasing the sirtuin level through genetic manipulation extends the lifespan of yeast, nematodes and flies. Deficiency of SIRT6 induces chronic inflammation, autophagy disorder and telomere instability. Also, these cellular processes can lead to the occurrence and progression of cardiovascular diseases (CVDs), such as atherosclerosis, hypertrophic cardiomyopathy and heart failure. Herein, we discuss the implications of SIRT6 regulates multiple cellular processes in cell senescence and aging-related CVDs, and we summarize clinical application of SIRT6 agonists and possible therapeutic interventions in aging-related CVDs.

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DNA Damage Response Mediates Pressure Overload–Induced Cardiomyocyte Hypertrophy

Cited by 38 publications

References 5 publications

Nuclear Hmgb1

Nuclear Hmgb1

Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes

SIRT6 in Senescence and Aging-Related Cardiovascular Diseases

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