Recently, clinical and experimental animal studies have demonstrated that doxorubicin induces cardiac atrophy, reflective of reduced left ventricular (LV) mass, LV function and cardiomyocyte size 3, 11. Cardiac sympathetic nerves provide trophic signal to the heart 4. Doxorubicin-induced cardiomyopathy is associated with cardiac sympathetic terminal abnormalities 8, 9, 10, as evidenced by decreased protein gene product (PGP) 9.5 and tyrosine hydroxylase, markers of cardiac innervation. A number of studies have shown that cardiac sympathetic nerve terminals are reduced in heart failure 5, 6, 7. The heart is extensively innervated by sympathetic nerves 4. Doxorubicin-induced cardiotoxicity is characterized by eccentric ventricular hypertrophy, dilated cardiomyopathy and congestive heart failure 2, 3. The anthracycline antibiotic doxorubicin has been used extensively as a potent anticancer chemotherapeutic agent, but its clinical use is limited by its cardiotoxicity 1. Nox2 mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy-both of which contribute to cardiac atrophy and failure after doxorubicin treatment. Myocyte autophagy was increased and myocyte size was decreased in WT doxorubicin mice, but not in Nox2 KO doxorubicin mice. In WT doxorubicin mice, myocardial oxidative stress was increased, myocardial noradrenergic nerve fibers were reduced, myocardial expression of PGP9.5, GAP43, tyrosine hydroxylase and norepinephrine transporter was decreased, and these changes were prevented in Nox2 KO doxorubicin mice. These alterations were attenuated in Nox2 KO doxorubicin mice. WT doxorubicin mice exhibited the decreases in survival rate, left ventricular (LV) wall thickness and LV fractional shortening and the increase in the lung wet-to-dry weight ratio 1 week after the injections. Nox2 knockout (KO) and wild-type (WT) mice were randomly assigned to receive a single injection of doxorubicin (15 mg/kg, i.p.) or saline. In this study, we tested whether NADPH oxidase 2 (Nox2) mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, resulting in cardiac atrophy and dysfunction in doxorubicin-induced heart failure. However, the underlying mechanisms remain to be fully elucidated. Doxorubicin has been used extensively as a potent anticancer agent, but its clinical use is limited by its cardiotoxicity.
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