The Oxygen-Rich Postnatal Environment Induces Cardiomyocyte Cell-Cycle Arrest through DNA Damage Response

Puente, Bao; Kimura, Wataru; Muralidhar, Shalini; Moon, Jesung; Amatruda, James F.; Phelps, Katherine J; Grinsfelder, D. Bennett; Rothermel, Beverly A.; Chen, Rui; Garcia, Joseph A.; Santos, Célio X.C.; Thet, Suwannee; Mori, Eiichiro; Kinter, Michael; Rindler, Paul M.; Zacchigna, Serena; Mukherjee, Shibani; Chen, David J.; Mahmoud, Ahmed I.; Giacca, Mauro; Rabinovitch, Peter S.; Asaithamby, Aroumougame; Shah, Ajay M.; Szweda, Luke I.; Sadek, Hesham A.

doi:10.1016/j.cell.2014.03.032

Cited by 740 publications

(816 citation statements)

References 95 publications

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“…8). This conclusion was also supported by the findings obtained from other studies that ROS accumulation could lead to DNA damage [55, 56]. …”

Section: Discussionsupporting

confidence: 85%

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Dong

et al. 2016

Mol Neurobiol

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DNA damage is associated with aging and neurological disorders, including Alzheimer’s disease. Isoflurane is a commonly used anesthetic. It remains largely unknown whether isoflurane induces DNA damage. Phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X) is a marker of DNA damage. We therefore set out to assess the effects of isoflurane on γH2A.X level in H4 human neuroglioma cells and in brain tissues of mice. Oxidative stress, caspase-activated DNase (CAD), and the p53 signaling pathway are involved in DNA damage. Thus, we determined the interaction of isoflurane with reactive oxygen species (ROS), CAD, and p53 to illustrate the underlying mechanisms. The cells were treated with 2 % isoflurane for 3 or 6 h. The mice were anesthetized with 1.4 % isoflurane for 2 h. Western blot, immunostaining and live cell fluorescence staining were used in the experiments. We showed that isoflurane increased levels of γH2A.X, cleaved caspase-3, and nucleus translocation of CAD and decreased levels of inhibitor of CAD (ICAD) and p53. Isoflurane enhanced the nucleus level of γH2A.X. Moreover, caspase inhibitor Z-VAD and ROS generation inhibitor N-acetyl-L-cysteine (NAC) attenuated the isoflurane-induced increase in γH2A.X level. However, NAC did not significantly alter the isoflurane-induced reduction in p53 level. Finally, p53 activator (actinomycin D) and inhibitor (pifithrin-α) attenuated and potentiated the isoflurane-induced increase in γH2A.X level, respectively. These findings suggest that isoflurane might induce DNA damage, as represented by increased γH2A.X level, via induction of oxidative stress and inhibition of the repair of DNA damage through the p53 signaling pathway.

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“…8). This conclusion was also supported by the findings obtained from other studies that ROS accumulation could lead to DNA damage [55, 56]. …”

Section: Discussionsupporting

confidence: 85%

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Dong

et al. 2016

Mol Neurobiol

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“…Consistent with previous reports of cardiac regeneration 23, 24 , microarray analysis revealed enrichment in expression of genes associated with the cell cycle and inflammation and reduced expression of genes involved in energy metabolism in AAV9:hYAP injected hearts. The gene expression profile of the latter hearts suggests the induction of an immature cardiac phenotype that is more proliferative.…”

supporting

confidence: 90%

Hippo in the Path to Heart Repair

Papizan

Olson

2014

Circulation Research

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“…Strong evidence indicates that oxidative stress is a major driver of the post-natal transition of cardiomyocytes the postmitotic state 41 . Previous studies implicated Tnni3k in responding to adult oxidative stress 34 , perhaps suggesting that Tnni3k similarly mediates cardiomyocyte response to oxidative stress experienced at birth.…”

Section: Discussionmentioning

confidence: 99%

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

Patterson¹,

Barske²,

Handel³

et al. 2017

Nat Genet

275

301

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Adult mammalian cardiomyocyte regeneration after injury is thought to be minimal. Mononuclear diploid cardiomyocytes (MNDCMs), a relatively small subpopulation in the adult heart, may account for the observed degree of regeneration, but this has not been tested. We surveyed 120 inbred mouse strains and found that the frequency of adult mononuclear cardiomyocytes was surprisingly variable (>7-fold). Cardiomyocyte proliferation and heart functional recovery after coronary artery ligation both correlated with pre-injury MNDCM content. Using genome-wide association, we identified Tnni3k as one gene that influences variation in this composition and demonstrated that Tnni3k knockout resulted in elevated MNDCM content and increased cardiomyocyte proliferation after injury. Reciprocally, overexpression of Tnni3k in zebrafish promoted cardiomyocyte polyploidization and compromised heart regeneration. Our results corroborate the relevance of MNDCMs in heart regeneration. Moreover, they imply that intrinsic heart regeneration is not limited nor uniform in all individuals, but rather is a variable trait influenced by multiple genes.

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The Oxygen-Rich Postnatal Environment Induces Cardiomyocyte Cell-Cycle Arrest through DNA Damage Response

Cited by 740 publications

References 95 publications

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway

Hippo in the Path to Heart Repair

Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration

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