Ang II-Induced Hypertension: Role of AT2 in End Organ Damage

Ang II 诱发的高血压：AT2 在终末器官损伤中的作用

• 批准号: 7896549
• 负责人: XIAO-PING YANG
• 金额: $ 22.15万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7896549
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; AGTR2 gene; Abbreviations; Acute; Adult; Agonist; Angiotensin II; Angiotensin II Receptor; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antibodies; Attenuated; Autacoids; Binding; Biomedical Engineering; Blood Vessels; Bradykinin; Brain natriuretic peptide; Breeding; CGP-42112; Cardiac; Cardiac Myocytes; Cardiovascular system; Chemosensitization; Chronic; Coculture Techniques; Congestive Heart Failure; Cyclic GMP; Data; Development; Dimerization; Dinoprostone; Doctor of Medicine; Endothelial Cells; Endothelium; Event; Extracellular Signal Regulated Kinases; Factor XIIa; Functional disorder; Growth; Guanosine; Heart; Heart Hypertrophy; Heterodimerization; High-Molecular-Weight Kininogen; Hypertension; Hypertrophy; Immunoprecipitation; Inflammatory; Infusion procedures; Kallikrein-Kinin System; Kininogenase; Kinins; Lead; Left Ventricular Remodeling; Left ventricular structure; Low-Molecular-Weight Kininogen; MAP Kinase Gene; Mediating; Membrane; Messenger RNA; Mitogen-Activated Protein Kinases; Molecular; Mus; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Nitric Oxide; Nitric Oxide Synthase; Organ; PTGS2 gene; Pathologic Processes; Patients; Peptidyl-Dipeptidase A; Phospholipase A2; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Plasma Kallikrein; Play; Prekallikrein; Principal Investigator; Prostate-Specific Antigen; Protein Kinase C; Protein Tyrosine Phosphatase; Protein phosphatase; Proteins; Renin-Angiotensin System; Research Personnel; Risk Factors; Role; Signal Transduction; Site; Small Interfering RNA; Testing; Therapeutic; Therapeutic Effect; Tissue Kallikrein; Tissues; Transgenic Organisms; Vasodilation; Vasodilator Agents; Yang; autocrine; blood pressure regulation; cyclooxygenase 2; enzyme activity; hypertensive heart disease; improved; knockout gene; lysosomal Pro-X carboxypeptidase; mRNA Expression; overexpression; prevent; programs; protective effect; receptor; receptor upregulation; response; vasoconstriction

Hypertension and cardiac hypertrophy are major risk factors for progression of cardiac dysfunction and development of congestive heart failure (CHF). Activation of the renin-angiotensin system, which leads to release of angiotensin II (Ang II), plays an important role in these pathological processes. Two major types of Ang II receptors, ATi and AT2, have been identified. The detrimental cardiac effects of Ang II are known to be mediated by activation of AT-i, since suppression of ATi with angiotensin II type 1 receptor antagonists (ATr ant) improves cardiac function, regresses left ventricular remodeling and prolongs survival in patients with HF. We and others have demonstrated that the effects of ATrant are mediated in part by activation of AT2. It has also been shown that activation of AT2 stimulates kinin release; however, the exact mechanism(s) involved is not well known. Nor do we know whether the cardioprotective effect of AT2 is due in part to a direct interaction with kinin B! and/or B2 receptors. Thus we propose to test the general hypothesis that chronic activation of AT2 causes kinin release by increasing kininogenase activity, includingtissue andplasma kallikrein. In addition to kinin release, activation ofAT2 potentiates the kallikrein-kinin system (KKS)by decreasing angiotensin-converting enzyme (ACE) and/or forming heterodimers with the B2 or B1 kinin receptors, leading to release of NO/cGMP and cardiovascular protection. We propose to use a combination of physiological, molecular, and pharmacological approaches and several lines of bioengineered mice to test this hypothesis. In Aim I, we will test the hypothesis that the AT2-induced increase in kinins is due to a) increased tissue kallikrein (TK)expression; b) increased kininogenase activity by activation of tissue prekallikrein to kallikrein; and c) activation of plasma prekallikrein via prolylcarboxypeptidase (PRCP), a known endothelial membrane-bound plasma prekallikrein activator. In Aim II, we will test the hypothesis that the cardiovascular protective effect of AT^ant is mediated in part by AT2-induced potentiation of kinins due to decreased ACE and/or a direct interaction with B2 due to heterodimerization. In Aim III, we will test the hypothesis that increased expression of AT2 and/or B, protects the heart from Ang ll-induced hypertension and cardiac remodeling post-Mi and contributes to the therapeutic effect of ATrant. In Aim IV, we will test the hypothesis that overexpression of AT2 in the vasculature is protective via release of kinins and NO, whereas high-level overexpression in CMs (exceeding AT! expression) is detrimental due to 1) increased kinins that act directly on CMs in an autocrine fashion, contributing to CM hypertrophy; and 2) AT2 interaction with or initiation of signaling events similar to AT^ activation. We believe these studies will enhance our understanding of the physiological and pathophysiological role of AT2 and how it interacts with the kallikrein-kinin system and leads to cardioprotection, as well as facilitate the development of better therapeutic strategies for hypertension and ischemic heart disease. Abbreviations: Ang II = angiotensin II; AT, and AT2 = angiotensin type 1 and type 2 receptors; ACE = angiotensin-converting enzyme; ant = antagonist; BK = bradykinin; B2 = B2 kinin receptors; BNP = brain natriuretic peptide; CHF = congestive heart failure; cGMP = guanosine 3',5'cyclic monophosphate; CMs = cardiomyocytes; COX-2 = cyclooxygenase-2; ECs = endothelial cells; EOD = end organ damage; ERK = extracellular signal-regulated kinase; HMWK = high-molecular weight kininogen; KKS = kallikrein-kinin system; LMWK = low-molecular-weight kininogen; LV = left ventricle; MAPK = mitogen-activated protein kinase; Ml = myocardial infarction; NO = nitric oxide; NOS = nitric oxide synthase; PGE2 = prostaglandin E2; PK = plasma kallikrein; PKC = protein kinase C; PLA2 = phospholipase A2; PTP = protein tyrosine phosphatase; PP2A = protein phosphatase-2A; PRCP = prolylcarboxypeptidase; RAS = renin-angiotensin system;Tg = transgenic; TK = tissue kallikrein; -/- = gene knockout. PHS 398/2590 (Rev.09/04, Reissued4/2006) Page197 Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Yang, Xiao-Ping, M.D./CarreterO,Oscar A., M.D. A.

高血压和心脏肥大是心脏功能障碍进展的主要危险因素和 充血性心力衰竭（CHF）的发展。肾素 - 血管紧张素系统的激活，导致 血管紧张素II（ANG II）的释放在这些病理过程中起重要作用。两种主要类型 ANG II受体ATI和AT2已被鉴定。已知ANG II的有害心脏影响是 通过激活AT-I的激活，因为用血管紧张素II型1型受体拮抗剂抑制ATI（ATR ANT）改善心脏功能，回归左心室重塑并延长HF患者的存活率。 我们和其他人已经证明，Atrant的影响部分是通过AT2的激活来介导的。它有 还表明，AT2的激活刺激了Kinin释放。但是，涉及的确切机制是 不知道。我们也不知道AT2的心脏保护作用是否部分归因于直接相互作用 与Kinin B在一起！和/或B2受体。因此，我们建议检验一般假设，即慢性激活的 AT2通过增加旋链酶活性（包括tissue and plasma kallikrein）而引起运动蛋白释放。在 除了释放Kinin 血管紧张素转换酶（ACE）和/或与B2或B1 Kinin受体形成异二聚体， 导致释放NO/CGMP和心血管保护。我们建议将 生理，分子和药理学方法以及几种生物工程的小鼠来对此进行测试 假设。在AIM I中，我们将检验以下假设：AT2诱导的Kinins的增加是由于A）增加 组织Kallikrein（TK）表达； b）通过激活组织前kallikrein的激活增加了依诺酶的活性 kallikrein; c）血浆prekallikrein通过丙酰羧肽酶（PRCP）激活，这是一种已知的内皮 膜结合的血浆prekallikrein活化剂。在AIM II中，我们将测试心血管的假设 AT^ant的保护作用是通过AT2诱导的基因素增强的AT介导的 和/或由于异二聚​​化而与B2的直接相互作用。在AIM III中，我们将检验以下假设 AT2和/或B的表达增加，可保护心脏免受ANG LL诱导的高血压和心脏的影响 改建后MI并有助于抗疗法的治疗作用。在AIM IV中，我们将检验假设 脉管系统中AT2的过表达是通过释放Kinin的保护性的，而高级的 CMS中的过表达（超过！表达）是有害的 CMS以自分泌方式，导致CM肥大； 2）AT2与或开始 信号事件类似于AT激活。我们认为这些研究将增强我们对 AT2的生理和病理生理作用以及它如何与Kallikrein-Kinin系统相互作用并引导 进行心脏保护，并促进更好地治疗策略以进行高血压和 缺血性心脏病。 缩写：ANG II =血管紧张素II； AT，AT2 =血管紧张素1型和2型受体； ace = 血管紧张素转换酶； ant =拮抗剂； BK = Bradykinin; B2 = B2 Kinin受体； BNP =大脑 亚钠肽； CHF =充血性心力衰竭； CGMP =鸟苷3'，5'Cyclic Monophathate; CMS = 心肌细胞； COX-2 =环氧合酶2; ECS =内皮细胞； EOD =最终器官损坏； ERK = 细胞外信号调节激酶； hmwk =高分子重量吉诺原； kks = kallikrein-kinin系统； lmwk =低分子量算力基因生成； lv =左心室； MAPK =有丝分裂原激活的蛋白激酶； ml = 心肌梗塞；否=一氧化氮； NOS =一氧化氮合酶； PGE2 =前列腺素E2; PK =等离子体 kallikrein; PKC =蛋白激酶C; PLA2 =磷脂酶A2; PTP =蛋白酪氨酸磷酸酶； pp2a = 蛋白质磷酸酶-2a; prcp = prolylcarboxypeptidase; RAS =肾素 - 血管紧张素系统; TG =转基因; tk =组织kallikrein; - / - =基因敲除。 PHS 398/2590（Rev.09/04，重新发行4/2006）Page197延续格式页面 首席调查员/计划总监（最后，第一，中间）：Yang，小平，M.D./Carretero，Soscar A.，M.D。 一个。