Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

Abstract

ABSTRACTBackgroundAnthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy and heart failure. Our laboratory previously reported that induction of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute Dox cardiotoxicity in zebrafish and in mice, and that potent Cyp1 inhibitors prevent cardiotoxicity. However, the role of Cyp1 enzymes in chronic Dox cardiomyopathy, as well as the mechanisms underlying cardioprotection associated with Cyp1 inhibition, have not been fully elucidated.MethodsThe Cyp1 pathway was evaluated using a small molecule Cyp1 inhibitor in wild-type (WT) mice, or Cyp1-null mice (Cyp1a1/1a2-/-,Cyp1b1-/-, andCyp1a1/1a2/1b1-/-). Low-dose Dox was administered by serial intraperitoneal or intravenous injections, respectively. Expression ofCyp1isoforms was measured by RT-qPCR, and myocardial tissue was isolated from the left ventricle for RNA sequencing. Cardiac function was evaluated by transthoracic echocardiography.ResultsIn WT mice, Dox treatment was associated with a decrease inCyp1a2and increase inCyp1b1expression in the heart and in the liver. Co-treatment of WT mice with Dox and the novel Cyp1 inhibitor YW-130 protected against cardiac dysfunction compared to Dox treatment alone.Cyp1a1/1a2-/-andCyp1a1/1a2/1b1-/-mice were protected from Dox cardiomyopathy compared to WT mice. Male, but not female,Cyp1b1-/-mice had increased cardiac dysfunction following Dox treatment compared to WT mice. RNA sequencing of myocardial tissue showed upregulation ofFundc1and downregulation ofCcl21cinCyp1a1/1a2-/-mice treated with Dox, implicating changes in mitophagy and chemokine-mediated inflammation as possible mechanisms of Cyp1a-mediated cardioprotection.ConclusionsTaken together, this study highlights the potential therapeutic value of Cyp1a inhibition in mitigating anthracycline cardiomyopathy.