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,2,The hot research of RAAS,Intracellular angiotensin II Ang II receptors,new agonist and antagonist ACE2 and ACE2 activator Renin and renin inhibitor RAAS and cardiac arrhythmia Brain angiotensin II,3,Classical circulating RAA
2、S,4,New expanded view of RAAS,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 intrac
3、ellular signaling leading to gene expression. receptor-dependent and independent,6,Ang II receptors,7,Ang II Receptors: AT1,AT1:decrease of plasma adiponectin; pro-inflammatory modulation; increased insulin secretion ; -cell apoptosis ; reduction of gluconeogenesis increased plasma triglycerides;,8,
4、AT2: New targets of neuronal disease?,The cellular targets of the AT2 receptor in neuronal 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
5、 injuries, diabetic neuropathy,neurodegenerative disorders and stroke,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
6、 mice,10,New possible ARBs,The most successful approach has been to modifyAT1-selective compounds to enhance their AT2 affinity. An acylsulfonamide group, is an isosteric replacement for the tetrazole ring, to provide AT2 affinity. New compounds known as “balanced” AT1/AT2 receptor antagonists(L-162
7、132) -equal affinity for the AT1 and AT2,11,Ang II receptors,12,AT4:an important target for drug 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 suc
8、h as Alzheimers disease, epilepsy and ischemia.-Heart Fail Rev. 2008 Sep;13(3):321-37,13,ACE2-Ang-(17)-Mas axis,14,ACE2-Ang-(17)-Mas axis,Angiotensin-converting enzyme 2 and Ang 17 may play an important role in cardiovascular physiology and pathophysiology, e.g. by modulating or counterbalancing exc
9、ess activity of the classical RAS. -Circ Res 2006; 98: 4637-Prog Biophys Mol Biol 2006; 91: 16398,15,Involvement of ACE2 in lung injury,ACE2 has been shown to function as a receptor of severe acute respiratory syndrome(SARS) coronavirus-Nat Med 2005; 11: 8759-J Mol Med 2006; 84: 81420 ACE2 may prote
10、ct against the potentially lethal lung injury associated with SARS-Nature 2005; 436: 1126,16,新成员,新靶点,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, 2
11、008; Gubala, David A. Ostrov and Mohan K. Raizada Jos A. Hernndez Prada, Anderson J. Ferreira, Michael J. Katovich, Vinayak Shenoy,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 fi
12、brosis in the SHR model of hypertension. Here for the first time a structure-based drug-discovery approach to enable rational development of enzyme activators.-Hypertension 2008;51;1312-1317,18,Ang-（1-7 ) and Mas agonist,The nonpeptide angiotensin-(17) receptor Mas agonist AVE-0991 Mas antagonist:A-
13、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;,19,Chymase :Recognition of Alternative pathways of Ang II generation,Chymase is enzymati
14、cally 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 in LVH,20,Renin and renin inhibitors,Great expectations are now generated by the introduction of renin inhibitors. The rece
15、nt introduction of the first orally effective renin inhibitor,aliskiren, has raised additional interest in new possibilities of almost complete blockade of RAS as a tool,21,Renin and renin inhibitors:DRIs,Early reports on the use of aliskiren are promising, showing at least, an antihypertensive effe
16、ct of aliskiren potent as those 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.,22,Antihypertensive Effects of Aliskiren Compared With Placebo,23,Renin and renin receptor: independe
17、nt of A II,24,Renin and Renin receptor,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 enzymeinhibitors (ACEIs) or angiotensin
18、receptor blockers (ARBs) are emerging as novel drugs for the prevention of AF.,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 neointimal formation caused by balloon injury
19、 have been focused mainly on experimental models of restenosis .,27,ARB and Balloon Injure,Hyper Res 2007; 10:971-978,28,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,29,New stu
20、dy:NAVIGATOR,Preliminary evidence that RAAS inhibitors 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.,30,RAAS and Ad
21、ipose 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 important source of both local a
22、nd circulating AGT,31,RAAS and Adipose tissue, obesity,The adipose RAS has ability to stimulateboth preadipocyte differentiation and lipogenesis in mature adipocytes . Angiotensin II enhances lipogenesis by directly increasing the activity and expression of key lipogenic enzymes, leading to increase
23、d triglyceride synthesis and storage and ultimately “fatter” fat cells.,32,Aldosterone and Myocardial/Renal Fibrosis,Experimental evidence indicates that aldosterone, besides its mineralcorticoid properties, directly contributes to accelerate myocardial and renal damage through promotion of cell gro
24、wth, fibrosis and inflammation. New receptor blocker:Eplerenone The Combination with ACEI and/or ARB,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
25、?,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.,35,Ongoing study about dual blockade,The Long-Term Impact of RAS Inhibition on
26、 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 eventually provide more definitive data on the effect of the combination of an ACE-I and an ARBon t
27、he progression of kidney disease.,36,Ongoing study about dual blockade,The VA NEPHRON-D study may eventually provide more definitive 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.,
28、37,Brain angiotensin II:,new developments, unanswered questions and therapeutic opportunities. There are two Angiotensin II systems in the brain.,38,Brain angiotensin II,Many questions remain. How is brain Angiotensin II formed, metabolized, and distributed? What is the role of brain AT2 receptors?
29、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?,39,Is the elevation of circulating AngII good for prevention of Stroke?,In prima
30、ry 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 thiazides and dihydropyridines, which increase Ang II.,40,Is the angiotensin II Type 2 recepto
31、r cerebroprotective?,AT2- and AT4-receptor-mediated brain-anti-ischemic mechanisms and propose a direct comparison of AT1-blockers with ACEIs to prove the clinical effectiveness of non-AT1-mediated mechanisms in stroke prevention, particularly in patients with a higher risk for stroke than for cardi
32、ac complications.,41,SUMMARY,The Renin Angiotensin System(s) are biologically 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.,42,Thank you,
