Antioxidant, EUK-8, Prevents Murine Dilated Cardiomyopathy

Abstract

Background: Mice lacking manganese-superoxide dismutase (Mn-SOD) activity exhibit the typical pathology of dilated cardiomyopathy (DCM). In the present study, presymptomatic and symptomatic mutant mice were treated with the SOD/catalase mimetic, EUK-8. Methods and Results: Presymptomatic heart/muscle-specific Mn-SOD-deficient mice (H/M-Sod2 −/− ) were treated with EUK-8 (30 mg · kg -1 · day -1 ) for 4 weeks, and then cardiac function and the reactive oxygen species (ROS) production in their heart mitochondria were assessed. EUK-8 treatment suppressed the progression of cardiac dysfunction and diminished ROS production and oxidative damage. Furthermore, EUK-8 treatment effectively reversed the cardiac dilatation and dysfunction observed in symptomatic H/M-Sod2 −/− mice. Interestingly, EUK-8 treatment repaired a molecular defect in connexin43. Conclusions: EUK-8 treatment can prevent and cure murine DCM, so SOD/catalase mimetic treatment is proposed as a potential therapy for DCM. (Circ J 2009; 73: 2125 -2134

Mitochondrial Quality Control as a Therapeutic Target

“…Mitochondrial targeting with peptide mimetics or lipophilic cationic agents (MitoQ, SkQ1) or manganese superoxide (SOD2) mimetics (Pucheu et al, 1996;van Empel et al, 2006;Kawakami et al, 2009;Iranzo, 2011) may also offer therapy for mitochondrial antioxidant protection. However, strategies to direct these compounds to the organ or cell type of interest at the apposite time are lacking, and their impact on the redoxregulation of mitochondrial biogenesis is unknown.…”

Cardiomyocyte-Derived Mitochondrial Superoxide Causes Myocardial Electrical Remodeling by Downregulating Potassium Channels and Related Molecules

“…The results are expressed as pmol H2O2 /min/mg protein. 9 To evaluate the in situ expression of ROS, fluorescent dihydroethydium (DHE, 10 μmol/L; Sigma) staining and 5-(and 6-)chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate, acetyl ester (DCF-DA, 10 μmol/L; Molecular Probes, Eugene, OR, USA) staining were performed. The specificity of DHE and DCF-DA signals for O2 .…”

“…8 They exhibit a 12.3-fold larger fibrotic area and a decreased expression of connexin 43 in their myocardium in comparison with age-matched wild-type (WT) mice. 9 In contrast, heterozygous heart/muscle-specific manganese superoxide-deficient (H/M-Sod2 +/-) mice exhibit no obvious difference in phenotypes in comparison with WT mice under normal circumstances, but exhibit an excessive response to hyperoxidative conditions, such as reperfusion injury. 10 However, the arrhythmogenicity of the response to the hyperoxidative state in these mice is unclear.…”

Mitochondrial Protection and the Reversal of Left Ventricular Remodeling

“…3 Previous studies have shown that EUK-8 prevents IR injury 4 and post-ischemic reperfusion arrythmias, 5 attenuates pathologic hypertrophic growth, 6 and ameliorates pressure-overload-induced heart failure. 7 In the present issue of the Journal, Kawakami et al 8 demonstrate that EUK-8 blunts the development of dilated cardiomyopathy (DCM), and also potently reverses established DCM in the hearts of muscle-specific SOD2 knockout (H/M-Sod2 −/− ) mice. In this transgenic mouse, the lack of cardiac mitochondrial SOD activity induces excessive generation of mitochondrial ROS, resulting in the accumulation of oxidative macromolecular damage, including oxidative damage to nuclear DNA.…”