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

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 (DOXþTRZ). 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 DOXþTRZ, left ventricular ejection fraction (LVEF) decreased from 75 � 3% at baseline to 46 � 2% at day 10 (P < 0.05). In the NOS3 � /� group, LVEF decreased from 72 � 3% at baseline to 35 � 2% at day 10 (P < 0.05). LVEF was RESUME