心力衰竭的信號通路

1、1,田小利人類群體遺傳室北京大學(xué)分子醫(yī)學(xué)研究所,,,,,,死亡,代償期,失代償期,惡化期,結(jié)構(gòu)和功能的改變---重塑,,高血壓，冠心病遺傳，心肌病瓣膜病，先心病,*,*,*,*,,心力衰竭,心力衰竭的誘因和病理過程,2,,,,,,激素、藥物、神經(jīng)遞質(zhì),膜受體,第二信使 Ca2+,離子通道,,活性肽,,,,,,,,,心力衰竭,心律失常,線粒體活性氧,,,,,心臟病相關(guān)基因,,,,,,活性肽,,,,(1),(1),,心

2、力衰竭,心力衰竭可能的發(fā)展基礎(chǔ),3,,心力衰竭,臨床診斷遺傳學(xué)通道電生理學(xué)神經(jīng)和信號轉(zhuǎn)導(dǎo),心肌重塑的關(guān)鍵分子,細(xì)胞水平鑒定動物模型計(jì)算機(jī)數(shù)字化模擬3-D結(jié)構(gòu)研究,作用機(jī)制及早期干預(yù)新藥靶點(diǎn)及可藥性早期診斷標(biāo)記的可能性,,目前主要研究的內(nèi)容,,,4,AOGEN,Renin,ACE,ANG I,ANG II,5,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

3、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Salt/water balance,Contraction of VSMC,Mitogenic effects,Neurotransmitter,Hormone-stimulation factor,Cardiac output,6,,

4、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,PLD,PLC,AII,a,g,b,,,,,,,,,,,,,,PC,PA,DAG,Choline,IP3,PIP2,,,PKC,Mek,Mapk,Stats,ER,,,Ca,++,,,,,,,Shc,Jaks,,,,,

5、,,,,,,,,SIE,C-fos,C-Jun,Stats,,,,,,,,,,,,,,,,,SOS,Grb2,Ras,Raf,,,,,,,,,GTP,C-myc,Egr,,Ca,++,,Ca,++,,Ca,++,,Ca,++,7,AOGEN,Renin,ACE,ANG I,ANG II,8,,,,,9,50,40,30,20,10,0,Captopril,Chymostatin,Cap + Chymo,Cap + Aprot,CV 11

6、974,%phenylephrine,ANG1 perfusion isolated aorta,Nishimura, 1998,Chymase:,Ang II forming enzyme in vitro,Found, cloned and characterized by Dr. Hidenori Urata,Urata, 1990,ACE,Chymase,Fe,Ad,Tian, 1996,Renin,Angiotensin

7、ogen,ACE,Angiotensin I,Angiotensin II,AT1,AT2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

8、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,AT1,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,AT2,,,,,10,,,,Angiotensinogen,Renin,Angiotensin 1,Angiotensin 2,Kininogen,Kallik

9、rein,Bradykinin,Inactive peptides,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,ACE,,,RAS,(AII/AT1),AS,(a1),,ETS,(ET-1/ETA),11,12,Angiotensin 1,Bradykinin,AcSDKP(N-acetyl-Ser-Asp-Lys-Pro),Angiotensin IICell growth. etc.,degraded frag

10、ments,degraded fragmentsActiate TGF-β signaling,13,Fleming I et al. Physiology. 2005;20:91-5.,ACE,NH2,ACE inhibitor,Extracellular,Cytosol,,,,,COOH,Nucleus,Gene expression(ACE, COX-2),,CK2,JNK,MKK7,P,JNK,cJun,cJun,P,cJu

11、n,P,cJun,P,cJun,P,AP-1,cJun,P,cJun,P,,,,,,,Clinical significance of this pathway is under investigation,Angiotensinogen (M235T)Together with ACE-D, associated male LVHCAD,AT1 (A1166C)Associated male LVH,14,15,ACE (I

12、/D)Earlier than 1994: tends to associatedLater than 1994: tends to not associatedLVH of man, not womanDegree, not frequency of LVHACEI treatmentQT dispersion, heart rate variabilityExercise-induced LHV,16,Ao,rt,a

13、,Lun,g,Ki,dn,ey,Brai,n,Li,v,er,L.,V,en,tr,ic,le,R.,ve,nt,ri,cl,e,Sk,. mu,scle,,,,,rAC,E,hA,CE,17,,AII (pg/g),AI on coronary artery flow,Cardiac AII,18,ACEI,19,20,Age > 10 months,col1,col3,GAPDH,NTGR,TGRL1172,TGRL1173,

14、Lisinopril,AcSDKP,,21,,,,,,,,,,ACE,TGF-β,TGF-R1,Smad3,Smad2,Smad4,,,Col,TGF-β,GAPDH,Smad3-p,Smad3,Smad2-p,Smad2,AcSDKP,NTGR,TGRL1172,TGRL1173,NTGR,TGRL1172,TGRL1173,Lisinopril,AcSDKP,NTGR,TGRL1172,TGRL1173,Lisinopril,AcS

15、DKP,22,23,,,,Definition of CG island in RAS promoters,24,,,,,ATG,TSS,5-UTR,1 kb,,,,,,,,,,,,,,,,,CG sites,CTGTCCCTGGCTCCTTCCCTGATCCCACCGCCAGCCTCACCCCACGGTTCCTCCATTGCCCCACCTCCCACTGCGCCGCCGGGCCTCTGCCAGGGTCAAGGGGCTTCCCCCCTC

16、TGGCAGCAGACGCCATGGTGCCGAGGTGGCCTCCACAACCGCCCTGTGCGCCAATAGGACAAGACTGTCCTCCCTCCCCCACACTTGTCACTTTGAGGGACACGTGGATGAGACAGGAAAACACAGGGGAGTGTGGAGACCTGAGGTGACTTGGAGCAAGCCTCTCAACCTGAGCGGCAATTTCTTCATCTGTAAAATGAGGGGGTTGTTCTCATC

17、TCTGAGGCTTTGTGTCGCTCTCAAAGCCTGCTAGCCTCGGGTTCTAGGACTCTGTTGGGATCGTGTGTGATGTTTTCTGCTGAGCGACGGCAGCCTGTGTCCTCGGGGGGAAAGAGGGCAGGCGCTCCAAAGCTCCTGCGCTCTGTGGCTCCCCCTCCCTCGCAGCCCCAAGCCCCAGGTGTGCCGGCCGCCCTGAGCCCCTCCAGCACCTCCCGG

18、AGGCGCCTGCAAGACACCTAAGGTCCCCGCCTCCCTCCTCTCCCCCCCGCCACACCCCTACCCCCGGCAGGCGACGTCCCCGCCCCTCGACCATGGCCTGGTGAAGAAGCCGGCCAGGCCCGATCAGCCCCATCCCCGCCGCACGAGCGGCGCCTGCGGACAGCTCCTGGGGCCCCGGCCTTGTCACTCCGGAGGCGGGAGGCTCCGGGGGGTCGGG

19、CTGGGAAGATCGAGCCGGAGGCCGCTAGGCTCCCAGGCCCCGGCCGAGGCTGCGCGGCCGCACGGTGGGCAGGCTCGGGTGTTCCGGCAAACTGCCGGGTCCCCATCTTCAAAAGAGAGGAGGCCCTTTCTCCAGCTTCCTCTGCGGGAGCCCGACCCAGCCCCATCCCGCCACCCCCGGGCTGCACCTCGGCCCCTCCCCGGCCCGCGCCCCTGC

20、CCGGGGCGGGCCAGGAACCTCGGCCCGCGCCGCTGGGGACTTTGGAGCGGAGGAGGAAGCGCGGCGGGGCGGGGGCGGGGGTGTGTCGGGTTTTATAACCCGCAGGGCGGCCGCGGCGCAGGAGAAGGGGCAGAGCCGAGCACCGCGCACCGCGTCATGGG,,ACE啟動子區(qū)CG島分析,25,26,AngiotensinogenReninACEAT1aAT2,7

21、469874588,甲基化分析的原理,27,mCG,亞硫酸氫鈉,mCG,PCR,CG,CG,UG,TG,CN,UN,TN,,,,克隆測序,直接測序,Characteristics of rats,,28,,,C,CG,29,100% protected = 100% methylation,How to quantify methylation,,C,WKY,SHR,30,Methylation of AOG,,CG,,CC,,

22、CG,,CC,31,,GC,,CC,,GC,,CC,WKY,SHR,Methylation of ACE (reversal sequence),32,33,34,Met,---,?,?,?,35,Several signaling pathways are involved in the pathogenesis of heart failureRAS plays a role in cardiac dysfunction thr