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: 7249767
• 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
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7249767
• 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; Binding; Biomedical Engineering; Blood Vessels; Bradykinin; Brain natriuretic peptide; Breeding; CGP-42112; Cardiac; Cardiac Myocytes; Cardiovascular system; Chemosensitization; Chronic; Coculture Techniques; Congestive; 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; Heart failure; 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; Personal Satisfaction; Phospholipase A2; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Plasma Kallikrein; Play; Prekallikrein; Principal Investigator; Prostate-Specific Antigen; Protein Kinase C; Protein Overexpression; 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; Vasodilation disorder; Vasodilator Agents; Yang; autocrine; cyclooxygenase 2; enzyme activity; hypertensive heart disease; improved; knockout gene; lysosomal Pro-X carboxypeptidase; mRNA Expression; 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.

高血压和心肌肥厚是心功能不全进展的主要危险因素， 充血性心力衰竭（CHF）的发展。激活肾素-血管紧张素系统，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。两种主要类型的 已经鉴定了Ang II受体AT 1和AT 2。已知血管紧张素II对心脏的有害作用是 由于用血管紧张素II 1型受体拮抗剂（ATr）抑制ATi， ant）改善HF患者的心功能，逆转左心室重构和存活率。 我们和其他人已经证明，ATrant的作用部分是由AT 2的激活介导的。它有 也显示AT 2的激活刺激激肽释放;然而，所涉及的确切机制是 不太出名。我们也不知道AT 2的心脏保护作用是否部分是由于直接相互作用 与kinin B一起！和/或B2受体。因此，我们建议测试的一般假设，慢性激活 AT 2通过增加激肽原酶的活性，包括组织和血浆激肽释放酶，引起激肽释放。在 除了激肽释放外，AT 2的激活通过降低激肽释放酶-激肽系统（KKS）的活性而增强KKS的活性。 血管紧张素转化酶（ACE）和/或与B2或B1激肽受体形成异二聚体， 导致NO/cGMP的释放和心血管保护。我们建议使用以下组合 生理学、分子学和药理学方法以及几种生物工程小鼠来测试这一点。 假说.在目的I中，我们将检验以下假设：AT 2诱导的激肽增加是由于a）增加 组织激肽释放酶（TK）表达; B）通过激活组织前激肽释放酶增加激肽原酶活性， c）通过脯氨酰羧肽酶（PRCP）激活血浆前激肽释放酶， 膜结合血浆前激肽释放酶激活剂。在目标II中，我们将检验心血管系统 AT_2的保护作用部分是由AT_2诱导的激肽增强介导的，这是由于ACE降低 和/或由于异源二聚化而与B2直接相互作用。在目标III中，我们将检验以下假设： 增加AT 2和/或B的表达，保护心脏免受Ang II诱导的高血压和心脏功能损害。 MI后重塑，并有助于ATrant的治疗效果。在目标四中，我们将检验假设 血管系统中AT 2的过表达通过释放激肽和NO具有保护作用，而高水平AT 2的过表达通过释放激肽和NO具有保护作用。 在CM中过度表达（超过AT！表达）是有害的，这是由于1）增加的激肽直接作用于 自分泌方式的CM，导致CM肥大;和2）AT 2与CM相互作用或启动 类似于AT 1激活的信号传导事件。我们相信这些研究会加深我们对 AT 2的生理和病理生理作用，以及它如何与激肽释放酶-激肽系统相互作用， 心脏保护，以及促进发展更好的高血压治疗策略， 缺血性心脏病 缩略语：Ang II =血管紧张素II; AT和AT 2 =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 =缓激肽; B2 = B2激肽受体; BNP =脑 利钠肽; CHF =充血性心力衰竭; cGMP =环磷酸鸟苷; CMs = 心肌细胞;考克斯-2 =环氧合酶-2; EC =内皮细胞; EOD =终末器官损伤; ERK = 细胞外信号调节激酶; HMWK =高分子量激肽原; KKS =激肽释放酶-激肽系统; LMWK =低分子量激肽原; LV =左心室; MAPK =丝裂原活化蛋白激酶; MI = 心肌梗死; NO =一氧化氮; NOS =一氧化氮合酶; PGE 2 =前列腺素E2; PK =血浆 激肽释放酶; PKC =蛋白激酶C; PLA 2 =磷脂酶A2; PTP =蛋白酪氨酸磷酸酶; PP 2A = 蛋白磷酸酶-2A; PRCP =脯氨酰羧肽酶; RAS =肾素-血管紧张素系统;Tg =转基因; TK =组织激肽释放酶; -/- =基因敲除。 PHS 398/2590（Rev.09/04，Reissued 4/2006）第197页续格式第页 主要研究者/项目负责人（末、中、首）：杨晓萍，医学博士/ CarreterO，Oscar A.，M.D. A.