Abstract
The molecular mechanisms underlying anthracyclines-induced cardiotoxicity have not been well elucidated. MiRNAs were revealed dysregulated in the myocardium and plasma of rats received Dox treatment. MicroRNA-34a-5p (miR-34a-5p) was verified increased in the myocardium and plasma of Dox-treated rats, but was reversed in rats received Dox plus DEX treatments. Human miR-34a-5p was also observed increased in the plasma of patients with diffuse large B-cell lymphoma after 9- and 16-week epirubicin therapy. Up-regulation of miR-34a-5p was observed in Dox-induced rat cardiomyocyte H9c2 cells. MiR-34a-5p could augment Bax expression, but inhibited Bcl-2 expression, along with the increases of the activated caspase-3 and mitochondrial potentials in H9C2 cells. MiR-34a-5p was verified to modulate Sirt1 expression post-transcriptionally. In parallel to Sirt1 siRNA, miR-34a-5p could enhance p66shc expression, accompanied by increases of Bax and the activated caspase-3 and a decrease of Bcl-2 in H9c2 cells. Moreover, enforced expression of Sirt1 alleviated Dox-induced apoptosis of H9c2 cells, with suppressing levels of p66shc, Bax, the activated caspase-3 and miR-34a-5p, and enhancing Bcl-2 expression. Therefore, miR-34a-5p enhances cardiomyocyte apoptosis by targeting Sirt1, activation of miR-34a-5p/Sirt1/p66shc pathway contributes to Dox-induced cardiotoxicity, and blockage of this pathway represents a potential cardioprotective effect against anthracyclines.
Highlights
Anthracyclines, used alone or in combination with other chemotherapeutic agents, are a class of antitumour drugs widely used for the treatment of a variety of cancers
We investigated the achievement of cardiac remodeling, expressions of apoptosis-related genes and miRNA profiling in the myocardium of SD rats received Dox or Dox combined with DEX treatment
The plasma cardiac troponin T was observed increased at 4 weeks and 8 weeks post-Dox treatment, but DEX could efficiently alleviate the increase of plasma cTnT (Fig. 1B)
Summary
Anthracyclines, used alone or in combination with other chemotherapeutic agents, are a class of antitumour drugs widely used for the treatment of a variety of cancers. Dexrazoxane (DEX) has been approved to prevent anthracycline-induced cardiomyopathy[6,7]. Recent studies have demonstrated that miRNAs participate in Dox-induced cardiomyopathy[16,17]. We investigated the achievement of cardiac remodeling, expressions of apoptosis-related genes and miRNA profiling in the myocardium of SD rats received Dox or Dox combined with DEX treatment. Sirt[1] was identified as a target gene of miR-34a-5p in Dox-induced cardiotoxicity. Through suppressing Sirt[1] to result in increased expression of Bax, activated caspase-3 and decreased expression of Bcl-2, contributing to Dox-induced apoptosis of cardiomyocytes. Our data demonstrated the NF-κB signal pathway mediates the upregulation of miR-34a-5p in cardiomyocytes exposed to Dox treatment. We identified miR-34a-5p/Sirt1/p66shc pathway mediates doxorubicin-induced apoptosis of cardiomyocytes and possibly provided a valuable way to protect against Dox-induced cardiotoxicity
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