raas系统研究的新热点陈明(英文版）

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,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,2021-4，广州,1,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,2,Classical circulating,RAAS,3,New expanded view of,RAAS,4,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 signaling leading to gene expression.,receptor-dependent and independent,5,Ang II receptors,6,Ang II Receptors:,AT1,AT1:,decrease of plasma adiponectin;,pro-inflammatory modulation;,increased insulin secretion;,-cell apoptosis;,reduction of gluconeogenesis,increased plasma triglycerides;,7,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 injuries,diabetic neuropathy,neurodegenerative,disorders and stroke,8,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,9,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 compounds known as“balanced,AT1/AT2 receptor antagonists(L-162132),-equal affinity for the AT1 and AT2,10,Ang II receptors,11,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 such as Alzheimers disease,epilepsy and ischemia.,-Heart Fail Rev.2021 Sep;13(3):321-37,12,ACE2-Ang-(17)-Mas axis,13,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 excess activity of the classical RAS.,-Circ Res 2006;98:4637,-Prog Biophys Mol Biol 2006;91:16398,14,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 protect against the potentially lethal lung injury associated with SARS,-,Nature 2005;436:1126,15,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,2021;51;1312-1317;originally published online Apr 7,2021;,Gubala,David A.Ostrov and Mohan K.Raizada,Jos A.Hernndez Prada,Anderson J.Ferreira,Michael J.Katovich,Vinayak Shenoy,16,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 of,hypertension.,Here for the first time a structure-,based drug-discovery approach to enable,rational development of enzyme activators.,-Hypertension 2021;51;1312-1317,17,Ang-1-7)and Mas agonist,The nonpeptide angiotensin-(17)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 2021;,18,Chymase,:R,ecognition,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 in LVH,19,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 in new possibilities of almost complete blockade of RAS as a tool,20,Renin and renin,inhibitors:DRIs,Early reports on the use of aliskiren are promising,showing at least,an antihypertensive effect 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.,21,Antihypertensive Effects of Aliskiren Compared With Placebo,22,Renin and renin receptor:independent of A II,23,Renin and Renin receptor,24,RAAS and cardiac arrhythmia,The renin-angiotensin-aldosterone system,(RAAS)has emerged as an important,hormonal system in the initiation and,pathogenesis