Figure 8.

Scheme showing that doxorubicin induces NADPH oxidase-derived oxidative stress, resulting in cardiac sympathetic nerve terminal abnormalities as evidenced by the decreases in norepinephrine (NE) histofluorescence and PGP9.5, GAP43, tyrosine hydroxylase (TH) and noradrenaline transporter (NET) protein expression, myocyte autophagy activation and myocyte apoptosis—all of which contribute to cardiac atrophy and failure. NADPH oxidase 2 (Nox2) KO attenuates cardiac sympathetic nerve terminal abnormalities, prevents activation of myocyte autophagy and reduces myocyte apoptosis, thereby improving cardiac atrophy and failure in mice after doxorubicin treatment. These findings suggest that the inhibition of NADPH oxidase, the improvement of cardiac sympathetic nerve terminal innervation and/or the reduction of myocyte autophagy could have beneficial effects in doxorubicin cardiomyopathy and heart failure.