Low-dose radiation differentially regulates protein acetylation and histone deacetylase expression in human coronary artery endothelial cells

Barjaktarović, Žarko; Merl-Pham, Juliane; Azimzadeh, Omid; Kempf, Stefan J.; Raj, Ken; Atkinson, Michael J.; Tapio, Soile

doi:10.1080/09553002.2017.1237059

Cited by 14 publications

(4 citation statements)

References 59 publications

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“…Both groups showed significant changes in the interferon signaling and Gα12/13 signaling. In line with previous in vitro and in vivo data, ,, irradiated cells showed radiation-induced changes in RhoA signaling.…”

Section: Resultssupporting

confidence: 91%

Radiation-Induced Endothelial Inflammation Is Transferred via the Secretome to Recipient Cells in a STAT-Mediated Process

et al. 2017

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Radiation is the most common treatment of cancer. Minimizing the normal tissue injury, especially the damage to vascular endothelium, remains a challenge. This study aimed to analyze direct and indirect radiation effects on the endothelium by investigating mechanisms of signal transfer from irradiated to nonirradiated endothelial cells by means of secreted proteins. Human coronary artery endothelial cells (HCECest2) undergo radiation-induced senescence in vitro 14 days after exposure to 10 Gy X-rays. Proteomics analysis was performed on HCECest2 14 days after irradiation with X-ray doses of 0 Gy (control) or 10 Gy using label-free technology. Additionally, the proteomes of control and radiation-induced secretomes, and those of nonirradiated HCECest2 exposed for 24 h to secreted proteins of either condition were measured. Key changes identified by proteomics and bioinformatics were validated by immunoblotting, ELISA, bead-based multiplex assays, and targeted transcriptomics. The irradiated cells, their secretome, and the nonirradiated recipient cells showed similar inflammatory response, characterized by induction of interferon type I-related proteins and activation of the STAT3 pathway. These data indicate that irradiated endothelial cells may adversely affect nonirradiated surrounding cells via senescence-associated secretory phenotype. This study adds to our knowledge of the pathological background of radiation-induced cardiovascular disease.

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Section: Resultssupporting

confidence: 91%

Radiation-Induced Endothelial Inflammation Is Transferred via the Secretome to Recipient Cells in a STAT-Mediated Process

et al. 2017

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“…RIHD arises from cell apoptosis and in ammatory and brotic processes, which can lead to the thickening of blood vessels and brotic scar tissue in the heart [37]. Several studies have linked altered lysine acetylation with the development of radiation induced damage [38]. In this study, acetylated protein levels were extensively elevated compared to sham-irradiated heart tissue.…”

Section: Discussionmentioning

confidence: 66%

Acetylation of ATP5f1c mediates cardiomyocyte senescence via metabolic dysfunction in radiation induced heart damage

Zeng

et al. 2022

Preprint

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Objective: Ionizing radiation (IR) causes heart senescence, which eventually manifests as radiation-induced heart damage (RIHD). Energy metabolism of cardiomyocytes is involved in senescence. This study attempts to explore radiation-induced senescence mechanisms through TMT-labeled proteomics.Methods: Echocardiography, senescence-associated secretory phenotype (SASP), telomere length and P21 expression were conducted to detect IR induced senescence. Total protein acetylation of irradiated heart apex and H9C2 cells was discovered by Western blotting compared with the control. To further investigate lysine acetylation alterations in irradiated heart proteins, proteomics of lysine acetylation was performed. Acetylated level of Atp5f1c was verified by Co-IP. The plasmids of the acetylated-mimicking Atp5f1c mutant (K55Q), deacetylated-mimicking Atp5f1c mutant (K55R) and WT were constructed and used for to transfect H9C2 cells to prove that acetylated Atp5f1c participated in energy metabolism and senescence. Deacetylation inhibitors, plasmid transfection and Co-IP were used to determine the mechanism of upstream regulation of Atp5f1c K55-Ac.Results: LVEF was decreased, SASP was elevated, telomere length was shortened and P21was overexpressed after IR. In addition, the total protein acetylation level significantly increased, and 69 proteins, including 90 sites, showed a lysine acetylation response to irradiation. The majority of the hyperacetylated proteins were related to energy metabolism. The ATP synthase γ subunit was hyperacetylated at the 55th lysine site and led to decreased ATP enzyme activity and synthesis decreased. Atp5f1c K55-Ac induced H9C2 metabolic dysfunction and senescence. Sirt4 and Sitr5, deacetylase inhibitors, mediated Atp5f1c K55-Ac deacetylation. Conclusion: IR induced cardiomyocyte senescence and energy metabolism disorder. Atp5f1c K55-ac, which is modulated by Sirt4 or Sirt5, might be a potential molecular target underlying RIHD.

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“…RIHD arises from cell apoptosis and inflammatory and fibrotic processes, which can lead to the thickening of blood vessels and fibrotic scar tissue in the heart [ 15 ]. Several studies have linked altered lysine acetylation to the development of radiation-induced damage [ 51 ]. In this study, acetylated protein levels were extensively elevated in irradiated heart tissue and H9C2 cells, compared to those in the control groups.…”

Section: Discussionmentioning

confidence: 99%

Acetylation of Atp5f1c Mediates Cardiomyocyte Senescence via Metabolic Dysfunction in Radiation-Induced Heart Damage

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective Ionizing radiation (IR) causes cardiac senescence, which eventually manifests as radiation-induced heart damage (RIHD). This study is aimed at exploring the mechanisms underlying IR-induced senescence using acetylation proteomics. Methods Irradiated mouse hearts and H9C2 cells were harvested for senescence detection. Acetylation proteomics was used to investigate alterations in lysine acetylation. Atp5f1c acetylation after IR was verified using coimmunoprecipitation (Co-IP). Atp5f1c lysine 55 site acetylation (Atp5f1c K55-Ac) point mutation plasmids were used to evaluate the influence of Atp5f1c K55-Ac on energy metabolism and cellular senescence. Deacetylation inhibitors, plasmids, and siRNA transfection were used to determine the mechanism of Atp5f1c K55-Ac regulation. Results The mice showed cardiomyocyte and cardiac aging phenotypes after IR. We identified 90 lysine acetylation sites from 70 protein alterations in the heart in response to IR. Hyperacetylated proteins are primarily involved in energy metabolism. Among them, Atp5f1c was hyperacetylated, as confirmed by Co-IP. Atp5f1c K55-Ac decreased ATP enzyme activity and synthesis. Atp5f1c K55 acetylation induced cardiomyocyte senescence, and Sirt4 and Sirt5 regulated Atp5f1c K55 deacetylation. Conclusion Our findings reveal a mechanism of RIHD through which Atp5f1c K55-Ac leads to cardiac aging and Sirt4 or Sirt5 modulates Atp5f1c acetylation. Therefore, the regulation of Atp5f1c K55-Ac might be a potential target for the treatment of RIHD.

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Low-dose radiation differentially regulates protein acetylation and histone deacetylase expression in human coronary artery endothelial cells

Abstract: This study shows that protein acetylation is an important mediator of radiation responses in human cardiac coronary endothelial cells. Increased knowledge of the endothelial response to radiation is crucial for the development of normal tissue-sparing modalities during radiation therapy.

Cited by 14 publications

References 59 publications

Radiation-Induced Endothelial Inflammation Is Transferred via the Secretome to Recipient Cells in a STAT-Mediated Process

Radiation-Induced Endothelial Inflammation Is Transferred via the Secretome to Recipient Cells in a STAT-Mediated Process

Acetylation of ATP5f1c mediates cardiomyocyte senescence via metabolic dysfunction in radiation induced heart damage

Acetylation of Atp5f1c Mediates Cardiomyocyte Senescence via Metabolic Dysfunction in Radiation-Induced Heart Damage

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