EUK-134, a superoxide dismutase and catalase mimetic, inhibits inflammatory cytokines, reduces myocyte necroptosis and improves left ventricular remodeling and function in heart failure after myocardial infarction in mice

Increased reactive oxygen species (ROS) play a crucial role in heart failure after myocardial infarction (MI), but the underlying mechanism remains poorly understood. In this study, we investigated whether EUK-134, a synthetic superoxide dismutase and catalase mimetic, reduces myocardial oxidative stress, inflammatory cytokines and myocyte necroptosis and apoptosis, leading to the improvement of left ventricular (LV) remodeling and function in heart failure after MI. Eight-week old C57BL/6J mice underwent MI or sham operation. The animals were randomized to receive EUK-134 (25 mg/kg, every other day, i.p.) or placebo for four weeks. In the MI placebo group, LV end-diastolic and end-systolic dimensions were increased, LV fractional shortening and LV ejection fraction were decreased, and these alterations were attenuated by the treatment of EUK-134. In the MI placebo group, myocardial expression of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress, inflammatory cytokines tumor necrosis factor-α, interleukin-1β and interleukin-6, and phosphorylated RIP1 (p-RIP1), p-RIP3 and p-MLKL, reflective of their respect kinase activities, markers of necroptosis, pro-apoptotic Bax protein, phosphorylated JNK (p-JNK) protein, cleaved caspase protein and myocyte apoptosis were markedly increased, and the increases were prevented by the treatment of EUK-134. Similarly, intracellular levels of ROS, necroptosis and apoptosis were increased in H9C2 cardiomyocytes under mimic ischemia and the increases were prevented by the EUK-134 treatment. These findings suggest that the superoxide dismutase and catalase mimetic EUK-134 prevents RIP1-RIP3-MLKL-mediated myocyte necroptosis and Bax/JNK-mediated myocyte apoptosis through inhibition of myocardial oxidative stress and inflammatory cytokines, leading to the improvement of post-MI LV remodeling and failure.