Extracellular superoxide dismutase regulates cardiac function and fibrosis

Abstract

Aims-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.Methods-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.Results-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.Conclusions-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.

Extracellular Superoxide Dismutase Ameliorates Skeletal Muscle Abnormalities, Cachexia, and Exercise Intolerance in Mice with Congestive Heart Failure

“…EcSOD-mediated protection against cardiac toxicity has been shown by Kliment et al where EcSOD global knockout mice showed exacerbated cardiac dysfunction, myocardial apoptosis and fibrosis following doxorubicin injection 41 . We have previously shown that adenovirus-mediated gene transfer of EcSOD in the heart elicits protective effects on cardiac function following myocardial infarction in rabbits 42 .…”

Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy

“…This assay was adapted from previously reported methods and used to quantify collagen content (20). Briefly, hearts from 3 and 6 mo posttreatment DM2 and age-matched control mice were dried in glass containers for 48 h at 100°C.…”

Impact of exercise training on redox signaling in cardiovascular diseases

“…Together, these antioxidant compounds maintain reactive species at nanomolar levels, preventing the disruption of redox homeostasis. SOD, responsible for the dismutation of O ÅÀ 2 to H 2 O 2 , plays a key role in the redox homeostasis under both physiological and pathological conditions (Kliment et al, 2009;Miriyala et al, 2012). This family of ubiquitous enzymes contains two main isoforms: MnSOD (manganese superoxide dismutase, located in the mitochondrial matrix) and Cu-ZnSOD (copper-zinc superoxide dismutase, located in the cytosol, extracellular space and mitochondrial inter membrane space).…”