| 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.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 as observed by impaired left ventricular hemodynamic performance parameters in DOX rats,but increasing MtFt expression,autophagy and cardiac function in Bay60 2770 pretreated group.Further,it also revealed significant reduction in ROS stress,P53ser15 activation and 3-Nitrotyrosine(3-NT)formation in Bay60 2770 pretreated H9C2 cardiomyoblast cell lines resulting in increased mitochondrial membrane potential,cell viability and the ensuing decreased apoptosis.And this study found Bay60 2770 activated sGC in DOX model dependent on ratio of sGC β1/sGC α1 but not significant change in protein level of sGC α1 and sGC β1.Also in our MtFt knock down(MtFt-KD)DOX cells by using siRNA construction,autophagysomes decreased significantly,but Bay60 2770 inversed the decreased level of autophagysomes.In conclusion,Bay60 2770 up-regulating ratio of sGC β1/sGC α1,activated sGC could improve cell viability,attenuate DOX induced ROS and mitochondrial membrane potential damage,associating with p-P53ser15 and up-regulated MtFt;since the improved cell-autonomous homeostasis mechanism,which also might have potential viability to decrease DOX induced secondary tumorigenicity.Together our findings reveal novel insights into the Bay60 2770 against the development of DOX mediated cardiotoxicity. |
