Abstract
Circadian rhythms disruption can be the cause of chronic diseases. External cues, including therapeutic drugs, have been shown to modulate peripheral-circadian clocks. Since anthracycline cardiotoxicity is associated with loss of mitochondrial function and metabolic remodeling, we investigated whether the energetic failure induced by sub-chronic doxorubicin (DOX) treatment in juvenile mice was associated with persistent disruption of circadian regulators. Juvenile C57BL/6J male mice were subjected to a sub-chronic DOX treatment (4 weekly injections of 5mg/kg DOX) and several cardiac parameters, as well as circadian-gene expression and acetylation patterns, were analyzed after 6weeks of recovery time. Complementary experiments were performed with Mouse Embryonic Fibroblasts (MEFs) and Human Embryonic Kidney 293 cells. DOX-treated juvenile mice showed cardiotoxicity markers and persistent alterations of transcriptional- and signaling cardiac circadian homeostasis. The results showed a delayed influence of DOX on gene expression, accompanied by changes in SIRT1-mediated cyclic deacetylation. The mechanism behind DOX interference with the circadian clock was further studied in vitro, in which were observed alterations of circadian-gene expression and increased BMAL1 SIRT1-mediated deacetylation. In conclusion, DOX treatment in juvenile mice resulted in disruption of oscillatory molecular mechanisms including gene expression and acetylation profiles.
Highlights
Cardiovascular physiology and disease, including myocardial infarction and sudden cardiac death, exhibit a 24 h periodicity (Litinski et al 2009; Mistry et al 2017; Tsimakouridze et al 2015)
SIRT3-activity rhythmicity is known for generating oscillations on the acetylation of key mitochondrial proteins (Peek et al 2013), while SIRT1 binds the core clock proteins BMAL1:CLOCK in a rhythmic manner promoting deacetylation of clock proteins, histones, and proteins involved in metabolic- and apoptotic processes (Bellet et al 2013; Nakahata et al 2008; Sahar et al 2014)
Protein extracts from HEK 293 cells co-transfected with flag-SIRT1, myc-BMAL1 and myc-CLOCK were immunoprecipitated with an anti-myc antibody, as described in Supplemental Material
Summary
Cardiovascular physiology and disease, including myocardial infarction and sudden cardiac death, exhibit a 24 h periodicity (Litinski et al 2009; Mistry et al 2017; Tsimakouridze et al 2015). While circadian disruptions are deleterious for the normal heart function (Knutsson et al 1986; Kohsaka et al 2014), NAD+ and SIRT1 seem to protect the myocardium against aging and oxidative stress (Alcendor et al 2007; Mericskay 2016) Based on these notions we sought to investigate whether pharmaceutical alterations of the cardiac circadian machi nery may result in an increased incidence of cardiovascular disease. The present study investigates whether DOX exposure in young mice could persistently interfere with the longterm transcriptional- and signaling circadian homeostasis, and how the metabolic- and energetic failure induced by a sub-chronic DOX treatment is integrated at the level of the circadian machinery
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