《内源性含硫气体分子的心血管调节英文课件幻灯PPT.ppt》由会员分享，可在线阅读，更多相关《内源性含硫气体分子的心血管调节英文课件幻灯PPT.ppt（45页珍藏版）》请在三一办公上搜索。
1、1,Endogenous Sulfur-containing Gaseous Molecules&Cardiovascular Regulation,Du Junbao,Tang Chaoshu Peking University Health Sciences Center,China,2,Endogenous gases,have important cardiovascular significancemove the cardiovascular medicine to a new phase,Continuous generationFast transmissionExtensiv
2、e actionShort half life timeLow molecular weight,3,E,H2S&Synthesis and Distribution,Intrinsic H2S content:Rat serum concentration:45.6 14.2 MH2S level in different blood vessels:Thoracic aorta:33.702.2 Portal vein:19.602.8 Pulmonary artery:5.310.7 Mesenteric artery:6.170.56 Coccygeal artery:8.120.85
3、(pmol/min/mg protein)H2S in myocardial tissues:18.64 4.49 pmol/min/mg wet tissueCSE shows expression in cardiovascular system,EMBO J,2001;BBRC 1997,2004;J Infect 2004,H2S is endogenously produced in cardiovascular system,4,Modulates cardiac contractility,Modulate proliferation and apoptosis of the v
4、ascular smooth muscle cells via MAPK pathway,Relax blood vessels,Relax pulmonary arteriesInhibits proliferation of the pulmonary arterial smooth muscle cells,Pulmonary Circulation,Systemic Circulation,Cardiac Functions,H2S&Cardiovascular Physiology,H2S exerts important cardiovascular physiologic fun
5、ctions,5,Some work we did on the role of H2S in pathogenesis of CVDs:,HypertensionHypoxic pulmonary hypertensionPulmonary blood flow-induced pulmonary hypertensionVascular calcificationHyperhomocysteinemia(HHcy)Endotoxic and septic shockMyocardial injury&coronary artery disease,6,In the rats with N-
6、nitro-L-arginine methyl ester(L-NAME)-induced hypertension,H2S/CSE pathway down-regulated,H2S&hypertension,Administration of a H2S donor attenuated SBP,J hypertens 2003,21(10):1879-1885,7,H2S&hypertension,In SHR,H2S/CSE pathway down-regulated,1,Plasma H2S level,WKY:(4813)M,SHR:(20 9)M,2,H2S producti
7、on in the aorta of SHR,WKY:(256)nmol/min/g wet tissues,SHR:(163)nmol/min/g wet tissues,3,CSEmRNA expression,WKY,SHR,Bioche Biophys Res Co 313(2004)2227,8,H2S donor decreased BP and lessened the vascular structural remodeling in the rat aorta,BP,H2S&hypertension,Biochem Biophys Res Co 313(2004)2227,W
8、KY control,SHR control,SHR+NaHS,Downregulation of H2S/CSE pathway is involved in the mechanisms for the development of hypertension,9,Relax blood vessels,Proliferation of smooth muscle cells,Apoptosis of smooth muscle cells,H2S,Inhibits,Induces,We found that possible mechanisms by which H2S regulate
9、s hypertension:,Vascular matrix remodeling,Inhibits,Hypertens Res,2008.in press,Biochem Biophys Res Co 313(2004)2227,H2S&hypertension,10,The ratio of the plasma H2S/Hcy decreased in children with hypertension,There was a negative correlation between systolic pressure and the ratio of plasma H2S/Hcy,
10、Chin Med J 2007;120(5):389-393,H2S&hypertension,Clinical Research,11,H2S and Cardiovascular Diseases,HypertensionHypoxic pulmonary hypertensionPulmonary blood flow-induced pulmonary hypertensionVascular calcificationHyperhomocysteinemia(HHcy)Endotoxic and septic shockMyocardial injury&coronary arter
11、y disease,12,In rats with hypoxic pulmonary hypertension,endogenousH2S/CSE pathway down-regulated obviously,H2S&hypoxic pulmonary hypertension,1,Plasma H2S level,3,CSEmRNA expression,2,Biochem Biophys Res Co 302(2003)810816,Con hypoxia hy+H2S,13,H2S donor decreased hypoxic pulmonary hypertension and
12、 attenuated RV hypertrophy,H2S&hypoxic pulmonary hypertension,Biochem Biophys Res Co 302(2003)810816,14,H2S donor relieved the hypoxic pulmonary vascular structural remodeling,H2S&hypoxic pulmonary hypertension,Microstructurechange,Ultrastructurechange,Biochem Biophys Res Co 302(2003)810816,control,
13、hypoxia,Hy+H2S,15,H2S inhibited hypoxic proliferation of pulmonary artery smooth muscle cell and induced hypoxic apoptosis of PASMCs,(PCNA IHC),control,hypoxia,Hy+H2S,Life Sciences 78(2006)1299 1309,H2S&hypoxic pulmonary hypertension,16,H2S reduced the collagen I and III abnormal accumulation in the
14、 pulmonary artery of the hypoxic rats,Collagen I,Collagen III,Life Sciences 78(2006)1299 1309,H2S&hypoxic pulmonary hypertension,17,Endogenous H2S is positively correlated with lung function,H2S&COPD,Clinical Research,Chest.2005;128(5):3205-11,Endogenous H2S decreased at the acute stage of COPD,N=77
15、,18,A rat model of high pulmonary blood flow-induced pulmonary hypertension by an abdominal aorta-inferior vena cava shunting operation,19,marker D1 D3 W1 W4 W8 W11,Up-regulated at the early stage of high pulmonary blood flow-induced pulmonary hypertension Down-regulated at the late stage of high pu
16、lmonary blood flow-induced pulmonary hypertension,H2S/CSE pathway exhibited the following changes:,Circ J,2005,H2S&pulmonary hypertension induced by high pulmonary blood flow,20,sham shunt+PAG shunt,*,shunt shunt+PAG sham sham+PAG,sham shunt shunt+PAG,4 w,Inhibition of endogenous H2S production prom
17、oted the pulmonary hypertension and pulmonary vascular structural remodeling,Life Sci,2007,841-849,H2S&pulmonary hypertension induced by high pulmonary blood flow,21,H2S donor reversed pulmonary hypertension and lessened pulmonary vascular structural remodeling,*,shunt shunt+NaHS sham sham+NaHS,sham
18、 shunt shunt+NaHS,Sham Shunt Shunt+NaHS,11 w,Acta Pharmacol Sin,2006,27(8):977986,H2S&pulmonary hypertension induced by high pulmonary blood flow,Abnormal H2S/CSE pathway participated in the different stages of PH induced by high pulmonary blood flow,22,Mechanism by which H2S attenuated pulmonary hy
19、pertension,Inhibiting proliferation of PASMCs via suppression of ERK/MAPK pathwayInducing apoptosis of PASMCs Enhancing degradation of extracellular matrixInteracting among gasotransmitters and vascular active peptides including ADM,ET and ANP,H2S&pulmonary hypertension induced by high pulmonary blo
20、od flow,23,Plasma H2S level decreased markedly Negative correlation between plasma H2S level and pulmonary artery pressure was created(R=-0.864),H2S&CHD with pulmonary hypertension,Clinical Research,control n=25,PH n=75,24,H2S and Cardiovascular Diseases,HypertensionHypoxic pulmonary hypertensionPul
21、monary blood flow-induced pulmonary hypertensionVascular calcificationHyperhomocysteinemia(HHcy)Endotoxic and septic shockMyocardial injury&coronary artery disease,25,H2S&Vascular calcification,Acta Pharmacol Sin 2006;27(3):299306,In vascular calcification model,H2S/CSE pathway down-regulated,26,H2S
22、&Vascular calcification,NaHS inhibited vascular calcification The mechanism involved the inhibition of osteopontin(OPN),Acta Pharmacol Sin 2006;27(3):299306,control,VDN,VDN+L,VDN+H,27,H2S and Cardiovascular Diseases,HypertensionHypoxic pulmonary hypertensionPulmonary blood flow-induced pulmonary hyp
23、ertensionVascular calcificationHyperhomocysteinemia(HHcy)Endotoxic and septic shockMyocardial injury&coronary artery disease,28,H2S&HHcy,Amino Acids(2008)34:573585,H2S decreased plasma Hcy level and reversed HCY-induced myocardial injury in HHcy rats,29,Hcy-induced mitochondrial respiration inhibiti
24、on,Hcy-induced mitochandrial enzyme dysfunction(SDH,COX),Hcy-stimulated H2O2 and superoxide anion production,Hcy-induced antioxidase inhibition(Mn-SOD),Hcy-induced endoplasmic reticulum stress,HHcy,H2S,Mechanism by which H2S antagonized Hcy-induced cardiovascular injury,Amino Acids(2008)34:573585,SD
25、H:succinic dehydrogenaseCOX:cytochrome oxidaseMn-SOD:manganese-superoxide dismutase,H2S&HHcy,30,H2S and Cardiovascular Diseases,HypertensionHypoxic pulmonary hypertensionPulmonary blood flow-induced pulmonary hypertensionVascular calcificationHyperhomocysteinemia(HHcy)Endotoxic and septic shockMyoca
26、rdial injury&coronary artery disease,31,H2S&shock,J Infection,2003,47:155-160,In endotoxic and septic shock,the increased H2S production was involved in its pathogenesis,32,H2S and Cardiovascular Diseases,HypertensionHypoxic pulmonary hypertensionPulmonary blood flow-induced pulmonary hypertensionVa
27、scular calcificationHyperhomocysteinemia(HHcy)Endotoxic and septic shockMyocardial injury&coronary artery disease,33,Endogenous H2S production was reduced in ISO-induced myocardial injury,H2S&Myocardial injury,1,Plasma H2S level,2,H2S production in the heart,3,CSEmRNA expression,Biochem Biophys Res
28、Co,318(2004)756763,34,H2S protects the structure and the contractility of the myocardiumThe mechanism is associated with the getting rid of free radicals,H2S&Myocardial injury,Biochem Biophys Res Co,318(2004)756763,35,Endogenous H2S production was inhibited in cardiomyopathy induced by adriamycin(AD
29、R),Plasma H2S level,H2S content in rat heart,H2S&Myocardial injury,36,NaHS-treatment improved ADR-induced depression of cardiac functions,H2S&Myocardial injury,37,NaHS-treatment lessened ADR-induced myocardial damage,H2S&Myocardial injury,38,NaHS-treatment inhibited ADR-induced oxidative stress by i
30、ncreasing antioxidase activity,NaHS:14umol/kg,Decreased production of H2S is involved in the pathogenesis of ADR-induced cardiomyopathy through inhibiting oxidative stress,H2S&Myocardial injury,39,H2S&CAD,Clinical Research,Decreased plasma H2S level correlate with the severity of CAD and coronary ar
31、tery lesions,SAP:Stable angina patientsUAP:Unstable angina patientsAMI:Acute myocardial infarction,40,There are other interesting studies on the role of H2S in the pathogenesis of cardiovascular diseases,Vascular neointima formation Myocardial infarctionHaemorragic shockH2S preconditioning for myoca
32、rdial injuryH2S postconditioning for myocardial injuryAngiogenesis Left-ventricular remodeling in SHR Others,FDU,FDU,US,CA,Sg,Z-Sg,Sg,CH,41,Conclusion,H2S is important for the homeostatic control of cardiovascular functions Abnormal metabolism and function of H2S contribute to the development of car
33、diovascular disease Correction of these abnormalities in the H2S/CSE would be beneficial for the prognosis of cardiovascular disease,42,Perspective,Clarify the significance of H2S as a gasotransmitter Provide insight into the mechanisms of many H2S abnormality-related diseases Seek for the way of pr
34、eventive and therapeutic strategies based on the biological effects of H2S,43,We demonstrated:SO2 could be endogenously generated in vascular tissues,SO2 could relax aortic rings,at least in part,through an L-type calcium channel,suggesting that it might act as a vasoactive molecule,44,We first explored the pathophysiological significance of endogenous SO2 in MCT-induced PH,Based on our studies,it is suggested that endogenous SO2 might play a pathophysiological and protective role,at least partially,in the process of MCT-induced PH,45,Thank you,
