Abstract
Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague–Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5–ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.
Highlights
Doxorubicin (DOX) is a highly effective chemotherapeutic agent used to reduce tumor burden in a wide variety of cancers [1]
At 9 days, all DOX-treated rats receiving either rAAV-dominant negative mutation of ATG5 (dnATG5) or saline, weighed considerably less and had a significantly reduced heart weight compared to saline-treated rats
The cytomegalovirus (CMV) promoter and AAV serotype 9 were used to drive gene expression of the rAAV-dnATG5 construct, and the vector was tagged with green fluorescent protein (GFP) to verify its presence in the myocardium
Summary
Doxorubicin (DOX) is a highly effective chemotherapeutic agent used to reduce tumor burden in a wide variety of cancers [1]. The clinical use of DOX is restricted due to the development of cardiotoxicity [2,3,4]. Current practices attempt to limit the cumulative dose of DOX in an effort to reduce the incidence of congestive heart failure (CHF) [5]. Retrospective studies evaluating DOX-related cardiac outcomes indicate that CHF occurs with greater frequency and with lower cumulative doses than previously recognized [5,6]. The onset of cardiomyopathy following DOX chemotherapy negatively impacts long-term cardiac outcomes in cancer survivors and severely limits treatment options for patients with relapsed or refractory disease [5]. Despite the prevalence and gravity of DOX-induced cardiac dysfunction there are currently no clinically-approved preventative strategies or standard of care practices for the management of DOX-related cardiomyopathy in cancer patients and survivors. Detailed understanding of the molecular mechanisms that drive DOX cardiotoxicity is necessary for the development of cardioprotective therapies
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