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The cardiotoxicity induced by the highlyeffective 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. For the development of seriously cardiotoxicity, doxorubicin is limited clinically in patients. Previous studies have attributed the cause of DOX mediated cardiotoxicity to mitochondrial iron accumulation and the ensuing production of reactive oxygen species (ROS) which seems to be independent to its DNA damage effect on antitumor. Interestingly, chemosensitization effect on cancer of soluble guanylate cyclase to cyclic guanosine monophosphate (sGC-cGMP)pathway induced tumor cells death, yet dramaticly, during heart failure sGC-cGMP signals protected cardiomyocytes survival. The present study investigates the effect of Bay60 2770, a more effective activator of oxidized soluble guanylate cyclase (sGC), and its role in alleviating DOX mediated cardiotoxicity.
SD rats administrated DOX (3.33mg/kg, 3 dose per week within 2 weeks, subsequently 2 weeks absence of treatment) with (w/o) Bay60 2770 pretreatments (5mg/kg, 3 dose per week, 1 hours prior DOX), then displayed heart dysfunction.H9C2 cardiomyoblast cells were treated with Bay60 2770 24 hours prior DOX. We used routine method to detecte echocardiography, cell ability, mitochondrial iron transfer and regulative proteins level, apoptosis, autophay, ROS and mitochondrial membrane potential.
Heart dysfunction was observed by impaired left ventricular hemodynamic performance parameters in DOX rats, but lowering apoptosis and increasing cardiac function in Bay60 2770 pretreated group marked with significantly high MtFt and ABCB8 expression, meanwhile with a trend of mitigatory p-P53 ser15 protein level. Further, it also revealed significant reduction in P53 activation and 3-Nitrotyrosine (3-NT) formation in Bay60 2770 pretreated H9C2 cardiomyoblast cell lines resulting in increased cell viability and the ensuing decreased apoptosis associated with recovery of mitochondrial membrane potential and decreased mitochondrial ROS. To better understand the cardioprotective role of Bay60 2770 against DOX, by using siRNA construction, we found Bay60 2770 amazingly inversed the decreased level of autophagysomes in our MtFt knock down (MtFt-KD) DOX cells.
Bay60 2770 could improve cell-autonomous mechanism to attenuate DOX induced cardiotoxcity and have potential viability to decrease DOX antitumor resistance and its secondary tumorigenicity. Together our findings reveal novel insights into the Bay60 2770 against the development of DOX mediated cardiotoxicity.