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The circadian clock protects against ionizing radiation‐induced cardiotoxicity
Author(s) -
Dakup Panshak P.,
Porter Kenneth I.,
Gajula Rajendra P.,
Goel Peeyush N.,
Cheng Zhaokang,
Gaddameedhi Shobhan
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901850rr
Subject(s) - circadian rhythm , cardiotoxicity , circadian clock , dna damage , medicine , apoptosis , cancer research , heart failure , ionizing radiation , endocrinology , biology , toxicity , dna , irradiation , genetics , physics , nuclear physics
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.