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The cardiotoxicity induced by the highly effective anti-cancer agent doxorubicin (DOX) involves increased oxidative stress, mitochondrial iron overload, DNA damage, autophagy, necrosis and apoptosis, underlining which also associated with its secondary tumorigenicity. soluble guanylate cyclase (sGC) signaling has protective effect on cardiovascular disease and chemosensitization effect on cancer. The present study investigates the role of Bay60-2770, a more effective activator of oxidized and heme-free sGC, and the role in alleviating DOX induced dilated cardiomyopathy.
H9c2 cardiomyocytes were treated with 10 μM Bay 60-2770 24hr prior to Dox (0.5-10 μM), and cell viability, 3-Nitrotyrosine and p-P53(ser15) were subsequently measured. In order to determine the role BAY60-2770 in ROS generation, we examined DCFH-DA and MitoSOX RED under DOX exposure. Also we did Cyto-ID autophagy detection. Additionally, 9-week-old male Sprague Dawley rats were orally administered with BAY60-2770 1 hour prior to every DOX treatment. Echocardiography and hemodynamic values were then analyzed. Autophagy proteins and mitochondrial iron regulating proteins expression levels were examined by western blot analysis.
BAY60-2770 ameliorated cell viability and 3-Nitrotyrosine induced by DOX in H9c2 cardiomyocytes. BAY60-2770 increased autophagosomes in DOX cells and up-regulated P62 expression level in heart tissue. p-P53(ser15), intracellular ROS and mitochondrial ROS attenuated by BAY60-2270 in DOX-treated H9c2 cells. BAY60-2270 enhanced the protein expression of Mitochondrial ferritin (MtFt) in DOX administered heart. Echocardiography showed that pre-treatment with BAY60-2770 significantly improved reduced LV function that is induced by DOX treatment.
BAY60-2770 reduces DOX-induced mitochondrial ROS generation and subsequent DNA damage by up-regulating MtFt. BAY60-2770 improved autophagy and cell viability, decreased cell death. BAY60-2770 ameliorated cardiac function. These novel results highlight the therapeutic potential of sGC signaling and MtFt to prevent doxorubicin induced cardiomyopathy.