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Extracellular superoxide dismutase regulates cardiac function and fibrosis
Corrine R Kliment1, Hagir B Suliman, Jacob M Tobolewski
1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Abstract:
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.
Insights
Extracellular superoxide dismutase (EC-SOD) is vital for normal heart function and protects against doxorubicin-induced cardiac damage, fibrosis, and apoptosis. Antioxidant AEOL 10150 effectively preserves cardiac function in mice treated with doxorubicin.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme with known protective roles in the lungs and heart during ischemia.
- The specific function of cardiac EC-SOD under normal physiological conditions and in response to injury, particularly doxorubicin-induced cardiotoxicity, remains incompletely understood.
- Doxorubicin-induced cardiotoxicity is a significant clinical concern, primarily mediated by oxidative stress.
Purpose of the Study:
- To investigate the critical role of EC-SOD in maintaining normal cardiac function and protecting the heart against doxorubicin-induced oxidative stress, fibrosis, and apoptosis.
- To evaluate the therapeutic potential of the antioxidant metalloporphyrin AEOL 10150 in mitigating doxorubicin-induced cardiac damage.
Main Methods:
- Comparison of cardiac function, morphology, fibrosis, and inflammation between wild-type and EC-SOD-null mice treated with doxorubicin.
- Echocardiography was employed to assess cardiac function (e.g., fractional shortening, LV dimensions).
- Histological staining, Western blot analysis, and hydroxyproline assays were used to quantify myocardial fibrosis and inflammation.
Main Results:
- EC-SOD-null mice exhibited baseline cardiac structural abnormalities (LV wall thinning, increased LV end-diastolic dimensions) but normal function.
- Doxorubicin treatment led to significant cardiac dysfunction, increased apoptosis, fibrosis, and inflammatory cell infiltration in EC-SOD-null mice compared to wild-type controls.
- Administration of AEOL 10150 effectively abrogated doxorubicin-induced loss of cardiac function and showed a trend towards reducing fibrosis in both wild-type and EC-SOD-null mice.
Conclusions:
- EC-SOD is essential for normal cardiac morphology and function, providing crucial protection against doxorubicin-induced oxidative stress, fibrosis, and apoptosis.
- The antioxidant AEOL 10150 demonstrates significant efficacy in protecting cardiac function against doxorubicin-induced cardiotoxicity in vivo.
- These findings highlight EC-SOD and antioxidant therapies as potential targets for managing oxidant-induced cardiac fibrosis.
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