富路韩颖哈尔滨医科大学附属第一医院心内科.ppt

富路韩颖哈尔滨医科大学附属第一医院心内科,雄激素对心衰雄鼠心脏交感神经重构的影响,TheFirstClinicalCollegeofHarbinMedicalUniversity,CardiacContractility,交感神经系统在心力衰竭中的作用,PeripheralPerfusion,SympatheticActivation,Apoptosis、Necrosis、Fibrosis、Hypertrophy,-Adrenergicdesensitization,SympatheticRemodelingCardiacRemodeling,ViciousCycle,TheFirstClinicalCollegeofHarbinMedicalUniversity,研究背景,Androgenbeneficial?deleterious?,女性,TheFirstClinicalCollegeofHarbinMedicalUniversity,研究背景,TheFirstClinicalCollegeofHarbinMedicalUniversity,雄激素的神经保护作用？,雄激素参与神经系统发育过程睾酮减轻缺氧缺血性脑损伤时大脑皮质神经细胞凋亡,TheFirstClinicalCollegeofHarbinMedicalUniversity,实验目的,观察内源性雄激素缺乏及生理剂量睾酮补充治疗对慢性心力衰竭雄鼠心脏交感神经重构的作用,实验方法,Wistar雄鼠60只（20020g）,去势/假去势术后1w给予异丙肾340mg/kg,共2次,正常组Control,S-Cas+Pla,Cas+Pla,Cas+Tes,Cas+Tes+Flu,血流动力学,心肌NE,血浆NE,免疫组化THNGF,WesternTHNGF,是NE合成的限速酶，其阳性表达可代表交感神经在心脏中的分布。,是神经营养因子家族的代表，对交感神经的生长、分化、存活、突触功能调控都有重要作用,实验结果,TheFirstClinicalCollegeofHarbinMedicalUniversity,血流动力学结果,与Control组比较，*P0.05；与Cas+HF+P组比较，P0.05。,表1各组大鼠血流动力学指标比较,TheFirstClinicalCollegeofHarbinMedicalUniversity,血浆及心肌NE,与正常组比较，*P0.05与Cas+HF+P组比较，P0.05,TheFirstClinicalCollegeofHarbinMedicalUniversity,心肌TH免疫组化染色,正常组,S-cas+Pla组,Cas+Pla组,Cas+Tes,Cas+Tes+Flu组,TheFirstClinicalCollegeofHarbinMedicalUniversity,心肌TH免疫组化染色,与正常组比较，*P0.05与Cas+HF+P组比较，P0.05,每组大鼠观察两张切片，每张切片计数5个（200）阳性率评定标准为结合表达面积和染色强度综合判定。,TheFirstClinicalCollegeofHarbinMedicalUniversity,心肌NGF免疫组化染色,正常组,S-cas+Pla组,Cas+Pla组,Cas+Tes组,Cas+Tes+Flu组,TheFirstClinicalCollegeofHarbinMedicalUniversity,心肌NGF免疫组化染色,与正常组比较，*P0.05与Cas+HF+P组比较，P0.05,每组大鼠观察两张切片，每张切片计数5个（200）阳性率评定标准为结合表达面积和染色强度综合判定。,*,*,*,*,TheFirstClinicalCollegeofHarbinMedicalUniversity,心肌THWesternBlot,与正常组比较，*P0.05；与Cas+HF+P组比较，P0.05,TH60kDa,GAPDH36kDa,Control,S-cas+Pla,Cas+Pla,Cas+Tes,Cas+Tes+Flu,TheFirstClinicalCollegeofHarbinMedicalUniversity,心肌NGFWesternBlot,与正常组比较，*P0.05；与Cas+HF+P组比较，P0.05,NGF13kDa,GAPDH36kDa,Control,S-cas+Pla,Cas+Pla,Cas+Tes,Cas+Tes+Flu,讨论,TheFirstClinicalCollegeofHarbinMedicalUniversity,心衰时心肌坏死、纤维瘢痕形成心脏交感神经轴索受其影响而出现功能障碍心衰时血浆NE作用于心肌细胞心肌中NGF的含量降低交感神经分布减少,TH、NGF，心脏交感神经分布密度交感神经失支配,动物,心衰交感神经重构,血浆NE水平，心肌NE含量心肌NE耗竭,TheFirstClinicalCollegeofHarbinMedicalUniversity,本研究显示,心肌NE含量,TH、NGF阳性神经密度,心肌TH、NGF蛋白表达,去势,生理睾酮替代,心脏交感神经重构,TheFirstClinicalCollegeofHarbinMedicalUniversity,Androgensignaltransduction,T,Targetcell,Nongenomiceffects,T,5-reductase,aromatase,DHT,T,E2,AR,ER/,Genomiceffects,CellfunctionGrowthDifferentiationProliferationapoptosis,TheFirstClinicalCollegeofHarbinMedicalUniversity,结论,在慢性心力衰竭雄性大鼠，内源性睾酮水平下降加重了心功能不全，并加重心脏交感神经重构；生理剂量睾酮替代治疗可以改善大鼠的心功能和心脏交感神经重构。这为睾酮补充治疗男性慢性心衰的临床可行性提供了理论依据。,TheFirstClinicalCollegeofHarbinMedicalUniversity,ThankYou!,LuFu,YingHanCardiovascularDepartment,FirstAffiliatedHospital,HarbinMedicalUniversity,China,Theeffectsoftestosteroneuponcardiacsympatheticfunctioninratswithinducedheartfailure,TheFirstClinicalCollegeofHarbinMedicalUniversity,CardiacContractility,ThesympatheticsysteminCHF,PeripheralPerfusion,SympatheticActivation,Apoptosis、Necrosis、Fibrosis、Hypertrophy,-Adrenergicdesensitization,SympatheticRemodelingCardiacRemodeling,ViciousCycle,TheFirstClinicalCollegeofHarbinMedicalUniversity,Background,Androgenbeneficial?deleterious?,Females,TheFirstClinicalCollegeofHarbinMedicalUniversity,Background,TheFirstClinicalCollegeofHarbinMedicalUniversity,Neuroprotectiveeffectsoftestosterone,TheFirstClinicalCollegeofHarbinMedicalUniversity,Aim,Thecurrentstudywasdesignedtodeterminewhethercastrationwithorwithouttestosteronereplacementresultedinchangesincardiacsympatheticnerveactivityinratswithinducedheartfailure.,Methods,60Wistarmalerats（20020g）,1waftercastration/sham-castration,ratsreceivedasubcutaneousinjectionofisoproterenolat340mg/kg,atotaloftwoinjections,Control,S-Cas+Pla,Cas+Pla,Cas+Tes,Cas+Tes+Flu,MyocardialNE,plasmaNE,Immunohisto-chemistryTHNGF,WesternBlotanalysisTHNGF,restinghemodyna-mics,Results,TheFirstClinicalCollegeofHarbinMedicalUniversity,Resultsofrestinghemodynamics,*P0.05vscontrolgroup；P0.05vsCas+Plagroup。,Table1resultsofrestinghemodynamics,TheFirstClinicalCollegeofHarbinMedicalUniversity,theplasmaandcardiacNEcontents,*P0.05vscontrolgroupP0.05vsCas+Plagroup,TheFirstClinicalCollegeofHarbinMedicalUniversity,ImmunohistochemicalstainingforTH,Controlgroup,S-cas+Plagroup,Cas+Plagroup,Cas+Tesgroup,Cas+Tes+Flugroup,TheFirstClinicalCollegeofHarbinMedicalUniversity,theTH-positivenervecelldensity,ThedensityofTH-labelednervefiberswasquantitativelyestimatedfrom10randomlyselectedfieldsatamagnificationof200.Thenervedensitywasmeasuredontracingsbycomputerizedplanimetry.,*P0.05vscontrolgroupP0.05vsCas+Plagroup,TheFirstClinicalCollegeofHarbinMedicalUniversity,ImmunohistochemicalstainingforNGF,Controlgroup,S-cas+Plagroup,Cas+Plagroup,Cas+Tesgroup,Cas+Tes+Flugroup,TheFirstClinicalCollegeofHarbinMedicalUniversity,theNGF-positivenervecelldensity,与正常组比较，*P0.05与Cas+HF+P组比较，P0.05,*,*,*,*,ThedensityofTH-labelednervefiberswasquantitativelyestimatedfrom10randomlyselectedfieldsatamagnificationof200.Thenervedensitywasmeasuredontracingsbycomputerizedplanimetry.,TheFirstClinicalCollegeofHarbinMedicalUniversity,theexpressionofTHprotein,*P0.05vscontrolgroup；P0.05vsCas+Plagroup。,TH60kDa,GAPDH36kDa,Control,S-cas+Pla,Cas+Pla,Cas+Tes,Cas+Tes+Flu,TheFirstClinicalCollegeofHarbinMedicalUniversity,theexpressionofNGFprotein,*P0.05vscontrolgroup；P0.05vsCas+Plagroup。,NGF13kDa,GAPDH36kDa,Control,S-cas+Pla,Cas+Pla,Cas+Tes,Cas+Tes+Flu,Discussion,TheFirstClinicalCollegeofHarbinMedicalUniversity,MyocardialischaemiaandcelldeathcardiacsympatheticnervefiberdysfunctionPlasmaNEaffectsmyocardiumNGFthedensityofcardiacsympatheticnerve,TH、NGF，thedensityofcardiacsympatheticnervescardiacsympatheticremodeling,SympatheticRemodelinginCHF,plasmaNE，myocardialNEexhaustofmyocardialNE,TheFirstClinicalCollegeofHarbinMedicalUniversity,Whatthereasearchtellus,myocardialNEcontent,TH/NGFpositivenervedensity,TH/NGFproteinexpression,Castration,Testosteronereplacement,Cardiacsympatheticremodeling,TheFirstClinicalCollegeofHarbinMedicalUniversity,Androgensignaltransduction,T,Targetcell,Nongenomiceffects,T,5-reducta