Extracellular
superoxide dismutase (EC-SOD) is an
antioxidant that protects the heart from
ischemia and the lung from
inflammation and
fibrosis. The role of cardiac EC-SOD under normal conditions and injury remains unclear.
Cardiac toxicity, a common side effect of
doxorubicin, involves oxidative stress. We hypothesize that EC-SOD is critical for normal cardiac function and protects the heart from
oxidant-induced
fibrosis and loss of function. C57BL/6 and EC-SOD-null mice were treated with
doxorubicin, 15 mg/kg (i.p.). After 15 days, echocardiography was used to assess cardiac function. Left ventricle (LV) tissue was used to assess
fibrosis and
inflammation by staining, Western blot, and
hydroxyproline analysis. At baseline, EC-SOD-null mice have LV wall thinning and increases in LV end diastolic dimensions compared to wild-type mice but have normal cardiac function. After
doxorubicin, EC-SOD-null mice have decreases in fractional shortening not apparent in WT mice. Lack of EC-SOD also leads to increases in myocardial apoptosis and significantly more LV
fibrosis and inflammatory cell infiltration. Administration of the
metalloporphyrin AEOL 10150 abrogates the loss of cardiac function, and potentially
fibrosis, associated with
doxorubicin treatment in both wild-type and EC-SOD KO mice. EC-SOD is critical for normal cardiac morphology and protects the heart from
oxidant-induced
fibrosis, apoptosis, and loss of function. The
antioxidant metalloporphyrin AEOL 10150 effectively protects cardiac function from
doxorubicin-induced oxidative stress in vivo. These findings identify targets for the use of
antioxidant agents in
oxidant-induced cardiac
fibrosis.