Improvement Of Hyperglycaemia Induced Mitochondrial Bioenergetics Damage And Inhibition Of ROS Induced Apoptosis By Phosphocreatine Protects Against Diabetic Cardiomyopathy Through JAK2/STAT3 Signaling Pathways In Vivo And In Vitro

BackgroundCardiovascular complications such as diabetic cardiomyopathy(DCM)are common in patients with diabetes mellitus(DM).Accumulated studies have shown that DCM thoroughly related to compromised mitochondrial energetics and increased generation of reactive oxygen species(ROS).Therefore,ongoing study is directed at developing strategies to protect cardiac mitochondria from diabetic complications,especially hyperglycemia.Phosphocreatine(PCr)provides its phosphate group to ADP that converts to ATP.For this reason,phosphocreatine is utilized as apharmacological treatment in human diseases that involve a failure of the cellular energy.However,whether PCr possesses the protective effects against DMC has not been reported yet.The purpose of the current studyWe hypothesized that PCr improves oxidative phosphorylation and electron transport capacity in mitochondria impaired by hyperglycemia in vivo and in vitro.Another aspect of this study was to evaluate the protective effect of PCr against DCM related to diabetes through JAK2/STAT3 signaling pathway.MethodsThe mitochondrial respiratory capacity of rats and H9C2 cells were measured by high-resolution respirometry(HRR)with the OROBOROS Oxygraph-2k.Levels of Bax,Bcl-2,expression proteins,caspase3,caspase9,cleaved caspase3,and cleaved caspase9,as well as JAK2/STAT3 signaling pathway,were determined by Western blotting.ROS generation,mitochondrial membrane potential(MMP)were measured with fluorescent probes.Enzymatic assays were determined by a spectrophotometer,Type 1 Diabetes mellitus was induced in Wister male rats by a single intraperitoneal injection of streptozotocin(80 mg/kg body weight).ResultsThe results revealed that PCr possessed protective effects against DCM injury by improving the mitochondrial bioenergetics and by positively exerting protective effects against DCM both in vivo and in vitro,not only improving diabetes symptom,resulting in changes of cardiac tissue H&E staining,but also ameliorating Biochemical changes,such as SOD,GSH and MDA Moreover,PCr exerts an antiapoptotic effect in vivo and in vitro,exposed to oxidative stress by hyperglycemia through JAK2/STAT3 signaling pathway.ConclusionPCr improves mitochondrial functions and exerts an antiapoptotic effect in vivo and in vitro,exposed to oxidative stress by hyperglycemia through JAK2/STAT3 signaling pathway.Thus,suggesting that PCr medication is a possible novel pharmacological strategy for cardioprotection.