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Previous studies have attributed the cause of doxorubicin (DOX) mediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of Bay60-2770, a more effective activator of oxidized soluble guanylate cyclase (sGC), and its role in alleviating DOX mediated cardiotoxicity.
H9c2 cardiomyocytes were pre-treated with BAY60-2770 followed by DOX, and cell viability and intracellular reactive oxygen species (ROS) were subsequently measured. In order to determine the role BAY60-2770 in mitochondrial ROS generation and mitochondrial membrane potential, we examined MitoSOX RED and TMRE fluorescence under DOX exposure. Additionally, rats were orally administered with BAY60-2770 1 hour prior to every DOX treatment. Left ventricular (LV) function and performance were then assessed by echocardiography. Mitochondrial iron regulating protein expression levels were examined by western blot analysis.
BAY60-2770 ameliorated cell viability and oxidative stress induced by DOX in H9c2 cardiac myocyte, which mediated by PKG activation. Mitochondrial ROS and TMRE fluorescence attenuated by BAY60-2270 in DOX-treated H9c2 cells. DOX-induced caspase-3 activation decreased after pre-treatment with BAY60-2770 both in vivo and in vitro. Echocardiography showed that pre-treatment with BAY60-2770 significantly improved reduced LV function that is induced by DOX treatment. BAY60-2270 enhanced the protein expression of Mitochondrial ferritin (MtFt) in DOX administered heart.
BAY60-2770 reduces DOX-induced mitochondrial membrane potential loss and subsequent apoptosis by up-regulating MtFt and improves cardiac function. These novel results highlight the therapeutic potential of BAY60-2770 to prevent doxorubicin cardiotoxicity.