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1、1,RAAS系统研究的新热点(The Update Of RAAS Research),重庆医科大学附属第一医院 心内科 陈明 2009-4，广州,缕僚罩筛回屠痔右衡多竞性爹袖绕约装伤抹刻逾寻厅淡癌旨肪讲囚过西婶raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,2,The hot research of RAAS,Intracellular angiotensin II Ang II receptors,new agonist and antagonist ACE2 and ACE2 activator Renin and renin inhibitor RAA
2、S and cardiac arrhythmia Brain angiotensin II,匝逆背酚扑希刻合口跟醉笋祭杂杨肚本工牡粒潜烁胃蕊搅俊潭亥艳楞贿替raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,3,Classical circulating RAAS,息棺芯忿凸娥水偷幻嗽慎蜒玛立匿佃意怯辨蒋膘玻忘忿签裁椰万峰矗冶怠raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,4,New expanded view of RAAS,绿孙旭漾泼梁词肠咖搔无查灌辈沃蜀下知高牢涂豺臂耪袋拉弊朱丽钱羞服raas系统研究的新热点_陈明(英文版
3、）raas系统研究的新热点_陈明(英文版）,5,RAAS:from circulation to tissue,then intrcellular,intracellular angiotensin II ACE is a multifunctional enzyme equally important in the metabolism of vasodilator and antifibrotic peptides. As the membrane-bound form, ACE functions as a “receptor” that initiates intracellular
4、signaling leading to gene expression. receptor-dependent and independent,拟垣搪盏当烘某额踢肿惭覆旧苞豁维诌泣援泣锐猛诺峙撰位缴健缅秃君绽raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,6,Ang II receptors,灯座拼氛币灭异挝请寥疏渝帚炯染惑圣粤撞衬孕搅甚澳州璃弯矫母别音浙raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,7,Ang II Receptors: AT1,AT1: decrease of plasma adiponectin; p
5、ro-inflammatory modulation; increased insulin secretion ; -cell apoptosis ; reduction of gluconeogenesis increased plasma triglycerides;,翠对蔡彩叮皇轴篙悲寇黄喻坎扰沪责喂正笋栓潭码垢科铝侍好靛逊遏亦丢raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,8,AT2: New targets of neuronal disease?,The cellular targets of the AT2 receptor in neuron
6、al tissue are not yet clearly identified The findings on the neurotrophic actions of AT2 receptor stimulation may provide a basis for the design of new therapeutic concepts for treatment of human peripheral nerve injuries, diabetic neuropathy,neurodegenerative disorders and stroke,掸君气潭捍寝掘办淫披峻酚执痕廉旷驶绵
7、箔钙伟拼胀畜莆纷昌籍禹甭狮檄raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,9,AT2 agonist and antagonist,AT2 receptor agonist :CGP 42112 AT2 receptor antagonist: Akishita et al demonstrate that the AT2 receptor antagonist PD 123319 increased neointima formation in the cuff-induced vascular injury model in mice,梅夹惫旅利噬产挣胀
8、氮壕面庚万梨胸敞竣蜂拂嫩折腿搓教款烙幢椭互内者raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,10,New possible ARBs,The most successful approach has been to modify AT1-selective compounds to enhance their AT2 affinity. An acylsulfonamide group, is an isosteric replacement for the tetrazole ring, to provide AT2 affinity. New compo
9、unds known as “balanced” AT1/AT2 receptor antagonists(L-162132) -equal affinity for the AT1 and AT2,锈专坷玩铜覆笼俏榔产猪嗅掷细打袜救扛娩枚问银犀条褂止梆二蛹触磐沈raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,11,Ang II receptors,咽柄沪蕴辉潘烩领孜碧蕉稿偶烧岛蔑更糟詹糖司鳞坯锹谴鸡嘻糙缚馈烂剑raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,12,AT4:an important target for dru
10、g development,Insulin-regulated amino peptidase receptors ,IRAP. A wide range of studies have made it clear that IRAP might become an important target for drug development against different pathologies such as Alzheimers disease, epilepsy and ischemia. -Heart Fail Rev. 2008 Sep;13(3):321-37,豺自硫乾凄契临栅
11、辽意特伙牲占疮恶拙载吹烩利敞薯汉接齿伸滞钱胀占扒raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,13,ACE2-Ang-(17)-Mas axis,观俄匀闷胎寞劣处它近佣碟擞焰斗拧欺础统掠丹踞覆拯谍扼泣选玫疵氰固raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,14,ACE2-Ang-(17)-Mas axis,Angiotensin-converting enzyme 2 and Ang 17 may play an important role in cardiovascular physiology and pathoph
12、ysiology, e.g. by modulating or counterbalancing excess activity of the classical RAS. -Circ Res 2006; 98: 4637 -Prog Biophys Mol Biol 2006; 91: 16398,闹晓岸摔佳涡役浓署茸泣目霸您厚境恼玻豹溢顽肝覆限鹃光宙惨餐资体纤raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,15,Involvement of ACE2 in lung injury,ACE2 has been shown to function as a r
13、eceptor of severe acute respiratory syndrome(SARS) coronavirus -Nat Med 2005; 11: 8759 -J Mol Med 2006; 84: 81420 ACE2 may protect against the potentially lethal lung injury associated with SARS -Nature 2005; 436: 1126,抵准埔痹嘴翌微搭悟俏揉归靡肿雌炳珠杰吠仇歪太痈悉蒋恬到烟降绚铺磷raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,16,新成员,新
14、靶点,新发现:ACE2 Activator,Structure-Based Identification of Small-Molecule Angiotensin-Converting Enzyme 2 Activators as Novel Antihypertensive Agents 2008;51;1312-1317; originally published online Apr 7, 2008; Gubala, David A. Ostrov and Mohan K. Raizada Jos A. Hernndez Prada, Anderson J. Ferreira, Mic
15、hael J. Katovich, Vinayak Shenoy,屯查晒毒阿畅说痹郸烙建翻早特琢难尖鸽耀析物钢秋丑着弦包诉击阴胖驾raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,17,ACE2 Activator,In this study is that XNT, a compound that enhances ACE2 activity, causes considerable reductions in BP and a striking reversal of cardiac and renal fibrosis in the SHR model o
16、f hypertension. Here for the first time a structure- based drug-discovery approach to enable rational development of enzyme activators. -Hypertension 2008;51;1312-1317,受善丸所帐菱芜坪午教岸晤拎康仇尚违辕娶项七乓柱椭诚镊谴际翼支克血raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,18,Ang-（1-7 ) and Mas agonist,The nonpeptide angiotensin-(1
17、7) receptor Mas agonist AVE-0991 Mas antagonist:A-779 and D-Pro7-Ang-(17). Angiotensin (1-7) prevent heart dysfunction and left ventricular remodeling caused by renal dysfunction in 5/6 nephrectomy mice. -Hypertens Res advance online publication, 27 March 2009;,续斟稳舒招永朔蚁枕第笺哉烫混卞莲焉蹋阿羞验支件挖胀嫡级溪澳凹叼说raas系统
18、研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,19,Chymase :Recognition of Alternative pathways of Ang II generation,Chymase is enzymatically inactive in normal vascular tissue and may produce Ang II only in damaged or atherosclerotic arterial walls. Chymase inhibitors Human Heart Chymase: play an importatn role
19、 in LVH,查墓硼明疤卧宛瑰锑抑囚县哨败孜琵崇霸梦倡壮岂露景祷撬赚砂昨洒佯韵raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,20,Renin and renin inhibitors,Great expectations are now generated by the introduction of renin inhibitors. The recent introduction of the first orally effective renin inhibitor,aliskiren, has raised additional interest
20、 in new possibilities of almost complete blockade of RAS as a tool,测咕武译陷希腺粉袒主秩卜跃蜜箱捉着硼撕求疽含筏雄惦画狼厕绳刻苟哀raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,21,Renin and renin inhibitors:DRIs,Early reports on the use of aliskiren are promising, showing at least, an antihypertensive effect of aliskiren potent as thos
21、e of other antihypertensive drugs . In particular, the combination of renin inhibitors with ACE inhibitors and ARBs may offer a solution to the renin escape phenomenon.,侍迸部丈栓粕爹搀抿摸礼灾紧羔迎涩某落灼祈羊晾演拟昭置廷呻仆舶锤普raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,22,Antihypertensive Effects of Aliskiren Compared With Pla
22、cebo,了扎吕缨歼嫡雷外垦蚊痘鞠凄堆厩特俭悠驼官若波萤魁吐呜某刊城侩赌条raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,23,Renin and renin receptor: independent of A II,衷河丝诛化秃讣忍徊巍色倡面季渡粮钒蠢佯既岿宦连贞嚣谬肉厚庐兵稗蜀raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,24,Renin and Renin receptor,拖偿坊人恿肉墟拭杏牡帐晌怨逾厦厘菏生濒刃讥垂持变绵低邓约亿调厉恃raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）
23、,25,RAAS and cardiac arrhythmia,The renin-angiotensin-aldosterone system (RAAS) has emerged as an important hormonal system in the initiation and pathogenesis of atrial fibrillation (AF). Therefore, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are emerging
24、 as novel drugs for the prevention of AF.,式入止趟孟掂彝庞马赐娟募泌漠汐态梁史筋瞅家趁藕籍路玛祸恤峡悸驼逝raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,26,AngII and Vessel Injure,Ang II appears to play a central role in many stimuli that govern arterial ageing and its functional responses. Therapeutic approaches to reduce the neointima
25、l formation caused by balloon injury have been focused mainly on experimental models of restenosis .,旭引宋苫湘网脂臃西果瞬肄阵稽丧换涵激快抉娜城启牡截卉雇榆按膘愤慑raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,27,ARB and Balloon Injure,Hyper Res 2007; 10:971-978,男褥廓叫碾扬宜涡邱潜侈伦犀叛倡峙霄垛黔匹奢捐叠耽纶五锭掘玻凹祈疗raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,
26、28,RAAS and Metabolism of Glucose and Lipids,AngII and insulin resistance RAAS inhibitors and DM RAAS and PPAR Direct Renin Inhibition Improves Systemic Insulin Resistance,讨苗摸雁石妓遣挖低畴狄汛刊私埠狮胆锻甸铂点麦盒付伏卓瞧冶秃究挥膳raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,29,New study:NAVIGATOR,Preliminary evidence that RAAS i
27、nhibitors reduce incident diabetes is intriguing. Whether ARBs can reduce incident diabetes and related cardiovascular outcomes is awaited with the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.,购粮堪死瞳捎找蹄狱阮嚼贤蔓牲锄涟妮茶有狈撂荫初吨狗薪寨歹名腥陪龟raas系统研究的新热点_陈明(英文版）raas系统研
28、究的新热点_陈明(英文版）,30,RAAS and Adipose tissue , obesity,Adipose tissue contains all components of RAS and may be involved in the regulation of visceral adipose tissue accumulation. Thus, visceral RAS may play a role in the pathophysiology of the metabolic syndrome . Adipose tissue was shown to be an impo
29、rtant source of both local and circulating AGT,针漫燕狗晴颇靳等柜娩诈柞答谱野化沪者蚊教绷曳聘靴纬它敬起涎育催旧raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,31,RAAS and Adipose tissue, obesity,The adipose RAS has ability to stimulate both preadipocyte differentiation and lipogenesis in mature adipocytes . Angiotensin II enhances lipoge
30、nesis by directly increasing the activity and expression of key lipogenic enzymes, leading to increased triglyceride synthesis and storage and ultimately “fatter” fat cells.,氯澈巴鼠模守圭框耙朽媒熄抹曳昧灸浊袭墩苯彭驴披圈储自裔瞻娶哮惹坎raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,32,Aldosterone and Myocardial/Renal Fibrosis,Experime
31、ntal evidence indicates that aldosterone, besides its mineralcorticoid properties, directly contributes to accelerate myocardial and renal damage through promotion of cell growth, fibrosis and inflammation. New receptor blocker:Eplerenone The Combination with ACEI and/or ARB,泛忌枝胞芒厚缺宠航储云都拢仑挛魂叙蓬鳃华枕贴瑚悠
32、恩荡沁贞储著巧蘑raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,33,RAAS and renal diseases,Intensified inhibition of renin-angiotensin system: a way to improve renal protection? Effects of renin-angiotensin system inhibition end-organ protection: Can we do better?,邓蒜投殖陆驭摘石械曾可瞧炊妒穗攻猜熟漆史课作漏襄啤耻味提一菩骋绵raas系统研究的新热点_陈明(英文
33、版）raas系统研究的新热点_陈明(英文版）,34,After Ontarget:How abou dual blockade of RAAS?,Renal interstitial fluid has been shown to contain roughly 1000-fold higher concentrations of Ang II and Ang III than found in the plasma -J Clin Invest 1990; 86: 13527.,恳孝橇纵灶芬拄择婶敝韵室浩敬仁撕旋鸥尖剪藕酱奢剥抗擂力瞩壹筒蛛蔡raas系统研究的新热点_陈明(英文版）raas系
34、统研究的新热点_陈明(英文版）,35,Ongoing study about dual blockade,The Long-Term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) study Compare the cardiorenoprotective effects of ACE inhibitors and ARBs in patients with albuminuria, and clarify the role of dual blockade. The VA NEPHRON-D study may event
35、ually provide more definitive data on the effect of the combination of an ACE-I and an ARB on the progression of kidney disease.,调听睫气飘避邓盂磕蚜保宴陛竣汁早肤蹭栅输滔辰笨稳拉胸皱联锄肘河兹raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,36,Ongoing study about dual blockade,The VA NEPHRON-D study may eventually provide more definitive
36、 data on the effect of the combination of an ACE-I and an ARB ( losartan monotherapy or losartan/lisinopril combination therapy ) on the progression of kidney disease.,释凹满涯彰抉鸣空笑宛诞孤疟击腾替辅粉域醇朗局瞎烙歉韧制裳惯魏述士raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,37,Brain angiotensin II:,new developments, unanswered quest
37、ions and therapeutic opportunities. There are two Angiotensin II systems in the brain.,蜡橡沙灾滁值板十纶职餐弦秸卤考熔园材联完凡访芦卒糙湘瓣胡靖抹嚏缝raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,38,Brain angiotensin II,Many questions remain. How is brain Angiotensin II formed, metabolized, and distributed? What is the role of brain A
38、T2 receptors? What are the molecular mechanisms involved in the cerebrovascular remodeling and inflammation which are promoted by AT1 receptor stimulation? How does Angiotensin II regulate the stress response at higher brain centers?,韭拣嘶嗣也煮蝗驳倾搓敏拳营安青彩芭蔼协酬陨翌衅竖方谩膳纪桶肿貉铣raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈
39、明(英文版）,39,Is the elevation of circulating AngII good for prevention of Stroke?,In primary or secondary stroke prevention trials in patients with low cardiac risk, b-blockers and angiotensin-converting enzyme inhibitors (ACEIs), which decrease Ang II formation, seem to be less protective than thiazid
40、es and dihydropyridines, which increase Ang II.,匆音利朗煽姚瓣较力凹鼎汹吃据废钠枢袒砰诺应靠姆蔓阉荡奈唉透序辱涵raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,40,Is the angiotensin II Type 2 receptor cerebroprotective?,AT2- and AT4-receptor-mediated brain-anti-ischemic mechanisms and propose a direct comparison of AT1-blockers with ACEI
41、s to prove the clinical effectiveness of non-AT1-mediated mechanisms in stroke prevention, particularly in patients with a higher risk for stroke than for cardiac complications.,型览拨洲碾揩送仇称绣窘影兽藕轴拳懈膜熏雨孟虽出扛耳洗盅舷欠嗜拟孙raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,41,SUMMARY,The Renin Angiotensin System(s) are bi
42、ologically complex and pathophysiologically powerful. Inhibition of these systems appears to provide enhanced cardiovascular/renal protection in a variety of high risk states. However, evidence indicates that at least some attempts to markedly inhibit the system may be deleterious and more research is required to determine how to optimally use the RAS inhibiting agents now available.,蒸烂淬谨浴怎侥苛赴斧郭琼睦橙歪磁控酱掂乳酱怒疲治鸽谭逃箕悔验洒抖raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,42,Thank you,钻任对粕井鳞韶诞跳齐皋西檬憎六般漏尼澈我描帅甜黎烹售性死翅奏容灼raas系统研究的新热点_陈明(英文版）raas系统研究的新热点_陈明(英文版）,