Congenital Absence of Nitric Oxide Synthase 3 Potentiates Cardiac Dysfunction and Reduces Survival in Doxorubicin- and Trastuzumab-Mediated Cardiomyopathy

Abstract Background Doxorubicin (DOX) and trastuzumab (TRZ) are highly effective chemotherapeutic agents in the breast cancer setting, limited by their cardiotoxic side effects. Among the potential mechanisms for this drug-induced cardiomyopathy, increased production of oxidative stress (OS) through a nitric oxide synthase 3 (NOS3)-dependent pathway has gained recent attention. The objective of the study was to determine the role of NOS3 and OS in a clinically relevant female murine model of DOX- and TRZ-induced heart failure. Methods A total of 120 female mice (60 wild-type [WT] and 60 NOS3 knockout [NOS3 −/− ]) were treated with either 0.9% saline, DOX, TRZ, or DOX with TRZ (DOX+TRZ). Serial echocardiography was performed for a total of 10 days, after which the mice were euthanized for histological and biochemical analyses. Results In WT female mice receiving DOX+TRZ, left ventricular ejection fraction (LVEF) decreased from 75 ± 3% at baseline to 46 ± 2% at day 10 ( P −/− group, LVEF decreased from 72 ± 3% at baseline to 35 ± 2% at day 10 ( P −/− female mice receiving DOX+TRZ than WT mice at day 10 ( P −/− female mice also demonstrated increased mortality after treatment with DOX+TRZ, corroborating the echocardiographic findings. Histological analysis demonstrated increased myofibrillar degradation and loss of cell integrity in NOS3 −/− female mice treated with DOX+TRZ. There was increased generation of oxidized phosphatidylcholine, a marker of OS, in NOS3 −/− female mice receiving DOX+TRZ compared with control mice. Conclusions Congenital absence of NOS3 potentiates the cardiotoxic side effects of DOX+TRZ in an acute female murine model of chemotherapy-induced cardiomyopathy.