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The circadian clock protects against ionizing radiation-induced cardiotoxicity.

ABSTRACT: Radiation therapy (RT) is commonly used to treat solid tumors of the breast, lung, and esophagus; however, the heart is an unintentional target of ionizing radiation (IR). IR exposure to the heart results in chronic toxicities including heart failure. We hypothesize that the circadian system plays regulatory roles in minimizing the IR-induced cardiotoxicity. We treated mice in control (Day Shift), environmentally disrupted (Rotating Shift), and genetically disrupted (Per 1/2 mutant) circadian conditions with 18 Gy of IR to the heart. Compared to control mice, circadian clock disruption significantly exacerbated post-IR systolic dysfunction (by ultrasound echocardiography) and increased fibrosis in mice. At the cellular level, Bmal1 protein bound to Atm, Brca1, and Brca2 promoter regions and its expression level was inversely correlated with the DNA damage levels based on the state of the clock. Further studies with circadian synchronized cardiomyocytes revealed that Bmal1 depletion increased the IR-induced DNA damage and apoptosis. Collectively, these findings suggest that the circadian clock protects from IR-induced toxicity and potentially impacts RT treatment outcome in cancer patients through IR-induced DNA damage responses.

SUBMITTER: Dakup PP

PROVIDER: S-EPMC9677419 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The circadian clock protects against ionizing radiation-induced cardiotoxicity.

Dakup Panshak P PP Porter Kenneth I KI Gajula Rajendra P RP Goel Peeyush N PN Cheng Zhaokang Z Gaddameedhi Shobhan S

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20200110 2

Radiation therapy (RT) is commonly used to treat solid tumors of the breast, lung, and esophagus; however, the heart is an unintentional target of ionizing radiation (IR). IR exposure to the heart results in chronic toxicities including heart failure. We hypothesize that the circadian system plays regulatory roles in minimizing the IR-induced cardiotoxicity. We treated mice in control (Day Shift), environmentally disrupted (Rotating Shift), and genetically disrupted (Per 1/2 mutant) circadian co ...[more]

PMID: 31919902

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Project description:Sugemule-3 (SD) is a traditional Chinese medicine with protective effect of myocardium. However, the underlying mechanisms of the effect had not been elucidated.In the present study, the serum of SD was prepared. A model of β-adrenergic agonist isoprenaline (ISO)-induced H9c2 cardiomyocytes injury was established in vitro. The changes in cell viability were examined to determine the available concentration of ISO and serum of SD. ELISA, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, and flow cytometry were used to detect the effect of serum of SD on oxidative stress and apoptosis. The expression levels of the mitochondria-dependent apoptotic pathway and mitogen-activated protein kinase signalling-related proteins were analyzed.Incubation with different dose of ISO (0.015, 0.01, 0.005, and 0.0025 mol/L) for 24 h caused dose-dependent loss of cell viability and 0.01 mol/L of ISO approximately reduced the cell viability to 50%. Pretreatment with 50 μ mol/L serum of SD effectively decreased the levels of ISO-induced cell toxicity. Serum of SD relived ISO-induced oxidative stress and apoptosis in H9c2 cardiomyocytes. A further mechanism study indicated that serum of SD inhibited the mitochondria-dependent apoptotic pathways and regulated the expression levels of Bcl-2 family. ISO activated ERK and P38, whereas serum of SD inhibited their activation.Serum of SD inhibits the ISO-induced activation of the mitochondria-dependent apoptotic pathway, oxidative stress, and ERK, P38 inactivation. Serum of SD is used for the treatment of ISO-induced cardiomyopathy.The serum of SD pretreatment significantly ameliorated ISO-induced H9c2 cardiomyocytes injuries.The protective effect related with apoptosis and oxidative stressInhibition of MAPK pathway was involed in serum of SD induced cardioprotection.The serum of SD is used for the treatment of ISO-induced cardiomyopathy. Abbreviations used: ELISA: Enzyme-linked Immunosorbent Assay; TUNEL: TdT-mediated dUTP nick end labeling; MTT: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, DMSO: dimethyl sulfoxide; MDA: Malondialdehyde; SOD: Superoxide Dismutase; GSH-Px: Glutathione peroxidase.

Project description:BACKGROUND AND PURPOSE: The clinical use of arsenic trioxide (As(2)O(3)), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As(2)O(3). The present study was designed to evaluate the effects of resveratrol on As(2)O(3)-induced apoptosis and cardiac injury. EXPERIMENTAL APPROACH: In a mouse model of As(2)O(3)-induced cardiomyopathy in vivo, QT intervals and plasma enzyme activities were measured; cardiac tissues were examined histologically and apoptosis assessed. In H9c2 cardiomyocyte cells, viability, apoptosis, generation of reactive oxygen species (ROS) and cellular calcium levels were measured. KEY RESULTS: In the mouse model, resveratrol reduced As(2)O(3)-induced QT interval prolongation and cardiomyocyte injury (apoptosis, myofibrillar loss and vacuolization). In addition, increased lactate dehydrogenase activity and decreased activities of glutathione peroxidase, catalase and superoxide dismutase were observed in the plasma of As(2)O(3)-treated mice; these changes were prevented by pretreatment with resveratrol. In As(2)O(3)-treated H9c2 cardiomyocytes, resveratrol significantly increased cardiomyocyte viability and attenuated cell apoptosis as measured by acridine orange/ethidium bromide staining, TdT-mediated dUTP nick end labelling assay and caspase-3 activity. As(2)O(3)-induced generation of ROS and intracellular calcium mobilization in H9c2 cells was also suppressed by pretreatment with resveratrol. CONCLUSIONS AND IMPLICATIONS: Our results showed that resveratrol significantly attenuated As(2)O(3)-induced QT prolongation, structural abnormalities and oxidative damage in the heart. In H9c2 cardiomyocytes, resveratrol also decreased apoptosis, production of ROS and intracellular calcium mobilization induced by treatment with As(2)O(3). These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As(2)O(3)-exposed patients.

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The circadian clock protects against ionizing radiation-induced cardiotoxicity.

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The circadian clock protects against ionizing radiation-induced cardiotoxicity.

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