Abstract
Doxorubicin is among the essential medicines with a wide antitumor spectrum, but its clinical application is limited by its cardiotoxicity. We recently discovered that ROCK1 is a key molecule in mediating cardiac remodeling in response to various stresses. To determine the roles of ROCK1 in doxorubicin cardiotoxicity, we gave three doses of doxorubicin injections to wild type (WT) and ROCK1−/− mice with one week intervals between treatments, the cumulative dose being 24 mg/kg. ROCK1−/− mice exhibited preserved cardiac function, reduced apoptosis, autophagy and fibrosis compared to the WT mice. To further determine the cellular mechanisms, we have examined the role of ROCK1 in cardiomyocytes using cardiomyocyte-specific knockout mice, MHC-Cre/ROCK1fl/fl, which partially reproduced the cardioprotective characteristics of ROCK1−/− mice, indicating that ROCK1 in both cardiomyocytes and non-cardiomyocytes mediates doxorubicin cardiotoxicity. To elucidate the molecular mechanisms, a detailed time course study after a single doxorubicin injection at 10 mg/kg was performed in ROCK1−/− and MHC-Cre/ROCK1fl/fl mice. The molecular analysis revealed that both ROCK1−/− and MHC-Cre/ROCK1fl/fl hearts exhibited significant reduction of doxorubicin-induced early responses including increased apoptotic (Bax) and autophagic (p62/SQSTM1 and LC3-II) markers, associated with reduced Beclin 1 phosphorylation on Thr119, supporting reduced Beclin 1-mediated autophagy initiation due to increased association of Beclin 1 with Bcl 2 or Bcl-XL in these hearts compared to the WT or ROCK1fl/fl mice. These results support that ROCK1 deficiency is cardioprotective against doxorubicin-induced cardiotoxicity at least in part through reducing Beclin 1-mediated autophagy initiation in cardiomyocytes and restoring autophagic flux to ameliorate doxorubicin cardiotoxicity.
Highlights
The anthracyclines, mainly doxorubicin, are among the most widely used and successful drugs to treat a wide spectrum of hematologic malignancies and solid tumors
To further determine the cellular mechanisms, we have examined the role of ROCK1 in cardiomyocytes using cardiomyocyte-specific knockout mice, myosin heavy chain (MHC)-Cre/ ROCK1fl/fl, which partially reproduced the cardioprotective characteristics of ROCK1-/mice, indicating that ROCK1 in both cardiomyocytes and non-cardiomyocytes mediates doxorubicin cardiotoxicity
Consistent with a previous report showing that mice with a heterozygous deletion of Beclin 1 are cardioprotective to doxorubicin through reducing the initiation of autophagy, which allows for the preservation of autophagic flux in the presence of impaired lysosome function by doxorubicin [16], our results demonstrate that attenuated autophagy initiation in ROCK1-/- mice results in limiting the accumulation of unprocessed autolysosomes and ameliorating doxorubicin cardiotoxicity
Summary
The anthracyclines, mainly doxorubicin, are among the most widely used and successful drugs to treat a wide spectrum of hematologic malignancies and solid tumors. Anthracycline-induced dosedependent and cumulative cardiotoxic side effects cause persistent and progressive damage to the cardiovascular system [1,2,3,4]. Their usefulness in cancer treatment is significantly compromised. Children and adolescents are vulnerable to anthracycline cardiotoxicity. About half of the young adult survivors of childhood cancer have received anthracyclines in their treatment [4,5,6,7]. Regardless of the severe cardiotoxicity, anthracyclines are still irreplaceable in cancer therapeutic schemes
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