The Protective Effect Of ATP-sensitive K~+ Channel On Radiation-induced Injury And Mechanism Exploration

1.BackgroundIonizing radiation(IR)is a ray that usually lead to extensive biological effects.As a"Double-edged sword",though IR has been used to produce energy,inhibit tumors and make weapons,its uncontrollable and inevitable harm is still of concern.Therefore the studies concerning radiation protection are in powerful need.In mechanism radiation induces damage to susceptive cells by directly breaking DNA double strands and indirectly up-regulating reactive oxygen species(ROS),which subsequently lead to further cells damage.In addition IR could stimulate immunocyte and activate inflammatory reaction.Targeting above mechanism some drugs have been particularlly developed.Such as radioprotectant targeting ROS and glucocorticoid remitting inflammation.However the side effects and low-pecificity are still obstacles for extensive application.ATP-sensitive K+(KATP)channel is a type of ATP-dependent and multiple subunits K+channel.Generally KATP consists of Kir6 inwardly rectifying potassium channel family and sulfonylurea receptor(SUR)subunits,which are members of the ATP-binding cassette transporter superfamily.KATP channels have been found to highly express in particular tissues including pancreaticβ-cell,brain,skeletal and smooth muscles,and blood vessel endothelium.Past studies concerning KATP channel mainly focused on its regulated function in insulin secretion by targeting pancreaticβ-cell and protective effect on ischemia reperfusion injury of myocardia.Recently some studies have investigated the effect of KATP channels on cellular protection and some researchers believe that KATP channels play an important role in ROS regulation.Accordingly in this study we investigated the relationship between KATP channels and radiation protection.By using KATP channels blocker Glibenclamide and opener Pinacidil we observed their effect on mice acute radiation sickness,radiation-induced liver and lung injury.Furthermore cytological experiments were conducted to verify the influence of KATP channels on radiation-induced cell damage.In mechanism we focused on the activation of intracellular ROS and Ca2+influx.Detecting the ROS-Akt pathway and PKC phosphorylation we revealed the mechanism of Glibenclamide protecting irradiated cells.2.Research contents(1)By blocking/opening KATP channels the survival rate of irradiated mice was tested.(2)By blocking/opening KATP channels the degree of mice acute radiation sickness was investigated(3)The effect of KATP channels on radiation-induced liver disease(RILD)and lung injury(RILI)were studied(4)Cellular radiosensitivity was detected by blocking/opening KATP channels and siRNA was used to confirm effect of KATP channels(5)Detecting intracellular ROS level and associated molecular pathway,we try to clarify the role of ROS in Glibenclamide-induced cellular protection(6)The Ca2+ influx and PKC activation were investigated to verify if Glibenclamide induces Ca2+ influx to stimulate Ca2+ influx phosphorylation so that inhibit radiation-induced apoptosis.3.Result(1)The KATP channels blocker GlibencLamide protect mice from radiation injury including promoting survival after irradiation,mitigate RILD and RILI.(2)Blocking KATP channels could reduce cellular radiosensitivity,enhance proliferation and inhibit apoptosis after irradiation.(3)Glibenclamide prevents acute radiation-induced hepatocyte injury via up-regulating intracellular ROS and subsequently activating Akt-NF-κB pathway.(4)KATP channels blocker glibenclamide inhibits radiation-induced apoptosis of vascular endothelial cell by increased Ca2+ influx and subsequent PKC activation.4.ConclusionShort-term blocking KATP channels with glibenclamide could mitigate radiation-induced injury of mice and inhibit cellular apoptosis by up-regulating intracellular ROS and elevating intracellular Ca2+ level to activate Akt/NF-κB pathway and PKC phosphorylation respectively.5.Innovation point and significance(1)To our knowledge this is the first investigation to relationship between KATP channels and radiation protection.We firstly demonstrated that Short-term blocking KATP channels could protect mice from radiation injury and reduce cellular radiosensitivity.(2)In mechanism we presented a new viewpoint that modest stimulation of ROS could protect rather than damage cells from radiation-induced damage.(3)Since glibenclamide protects mice from radiation injury we propose a reference of glibenclamide use for radiotherapy patients complicated with diabetes...