Peptide Therapy for Pulmonary Arterial Hypertension

肺动脉高压的肽疗法

• 批准号: 7929254
• 负责人: JAWAHARLAL M. PATEL
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929254
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Phosphoinositide Dependent Protein Kinase-1; Adult Respiratory Distress Syndrome; Altitude; Amino Acid Sequence; Amino Acids; Animal Model; Arteries; Attenuated; Binding; Biological Availability; Blood Vessels; Blood flow; Cardiac; Cardiac Output; Chemicals; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Treatment; Combined Modality Therapy; Conscious; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Data; Development; Disease; Dissociation; Dose; Etiology; Event; Exposure to; Failure; Functional disorder; GTP-Binding Proteins; Guanosine; HIV Infections; Health; Heart; Heart Diseases; Heart failure; Hematocrit procedure; Human; Human Resources; Hydrolysis; Hypertension; Hypoxia; Implant; Injury; Investigational Therapies; Lead; Legal patent; Low Cardiac Output; Lung; Lung diseases; Medial; Mediating; Mediator of activation protein; Modeling; Molecular; Monitor; Morbidity - disease rate; Motion; Nitric Oxide; Nitric Oxide Synthase; Obesity; Obstruction; Patients; Peptide Sequence Determination; Peptides; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphorylation; Phosphotransferases; Physiological; Play; Population; Prevalence; Production; Proto-Oncogene Proteins c-akt; Pulmonary Circulation; Pulmonary Vascular Resistance; Pulmonary artery structure; Rattus; Regimen; Regulation; Reporting; Right Ventricular Hypertrophy; Right lung; Right ventricular structure; Risk Factors; Role; Route; Schistosomiasis; Signal Transduction; Smoking; Smooth Muscle Myocytes; Telemetry; Testing; Therapeutic; Therapeutic Agents; Thick; Toxic effect; Toxin; Treatment Efficacy; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vascular remodeling; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Ventricular; Veterans; base; caveolin 1; cigarette smoking; clinically relevant; combat; experience; hemodynamics; human NOS3 protein; improved; indexing; inhibitor/antagonist; innovation; intraperitoneal; knockout animal; lung injury; mortality; novel; novel strategies; novel therapeutic intervention; patient population; peptide P3; phosphoric diester hydrolase; pre-clinical; pressure; pulmonary arterial hypertension; pulmonary artery endothelial cell; response; sildenafil; subcutaneous; success; synthetic peptide; treatment strategy; vascular endothelial dysfunction; vasoconstriction

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PH) is a devastating disease of diverse etiology that contributes to high morbidity and mortality of patients with various lung and heart diseases. PH is characterized by vascular obstruction and variable presence of vasoconstriction, leading to a sustained increased pulmonary vascular resistance, vascular remodeling, right ventricular (RV) failure, and low cardiac output. Despite its profound clinical consequences, therapeutic advances over the past 25 years have modestly improved survival of PH patients. The combined use of available drugs to maximize the clinical benefit is an emerging strategy for the treatment of PH. Although failing RV is a common clinical problem in PH, currently RV-specific experimental therapies are not available. One of the major physiologic mechanisms of PH suggests endothelial dysfunction that causes diminished nitric oxide (NO) production and NO/cyclic guanosine 5' monophosphate (cGMP)- dependent vasorelaxation in the pulmonary circulation. Alternatively, pulmonary vascular cGMP levels can also be elevated via inhibition of phosphodiesterase type 5 (PDE5) to achieve a similar response. Since PDE5 expression has been shown to be increased in the lungs and RV of PH patients, targeted efforts to increase NO production and PDE5 inhibition can counteract vasoconstriction that contributes to increased afterload in failing heart of PH patients. We have identified a fifteen amino acid (FKSRNSRWSCRIKSR) synthetic peptide (P3) that enhances the catalytic activity of endothelial NO synthase (eNOS) and inhibits cGMP-specific PDE5 in pulmonary artery endothelial cells as well as in pulmonary artery smooth muscle cells. Preliminary data indicate that P3 stimulation increases intracellular NO release, inhibits rate of cGMP hydrolysis, and attenuates increase in pulmonary artery pressure (PAP) but not systemic artery pressure (SAP) monitored in telemetry implanted conscious rat model of hypoxia-induced PH. Based on these preliminary data, we hypothesize that P3 treatment with its unique dual action as NO releasing PDE5 inhibitor offers novel therapeutic approach for the treatment of PH. To test this hypothesis, the specific aims of this study are to: (I) identify P3-mediated molecular events associated with increased eNOS activity and NO production with specific focus on Ca2+ release, activation of signaling modules [phospatidylinositide (PI) 3-kinase (PI3K), protein kinase B (PKB or Akt), protein kinase A (PKA), and Src tysorine kinase (SrcK)], phosphorylation of caveolin-1 (Cav-1) and/or eNOS, and Cav-1/eNOS dissociation, (II) elucidate whether P3 mediated inhibition of PDE5/cGMP hydrolysis is associated with Ca2+ release, activation of PI3K, protein kinase G (PKG)/PKA signaling, phosphorylation of PDE5, and/or inhibition of cGMP binding of PDE5, and (III) determine therapeutic potential of P3 using a physiologically-relevant hypoxia-induced animal model of PH with specific focus on assessment of bioavailability, dosing regimen, efficacy, and toxicity of P3 therapy on the progressive and regressive pulmonary hemodynamic modulations (increased PAP, SAP, cardiac output/cardiac index, hematocrit, and RV hypertrophy) and vascular remodeling associated with PH as well as toxicity. Confirmation of the mechanism-based physiological approach for NO releasing PDE5 inhibitor function of this novel peptide in preclinical animal model is innovative for progression towards Phase I clinical trial for treatment of PH. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health: Pulmonary vascular disease and hypertension are common in the VA patient population because of the high incident in this population of cigarette smoking-related chronic obstructive pulmonary disease (COPD). Vascular complications of pulmonary injury, including PH, are also frequently observed in combat casualty victims who develop adult respiratory distress syndrome (ARDS). In addition, exposure of veterans and current active duty personnel to multiple risk factors including high altitude, drugs, chemicals, HIV infection, and schistosomiasis can cause lung injury and progressive development of PH. Identification of mechanism-based unique therapeutic agent with NO releasing PDE5 inhibitory function offers a novel strategy for treatment of PH.

描述(由申请人提供)： 肺动脉高压(PH)是一种多种病因的破坏性疾病，导致各种肺病和心脏病患者的高发病率和死亡率。PH的特点是血管阻塞和不同程度的血管收缩，导致肺血管阻力持续增加、血管重构、右室衰竭和低心输出量。尽管其临床后果深远，但在过去的25年里，治疗的进步略微改善了PH患者的存活率。联合使用现有药物以最大限度地提高临床效益是治疗PH的一种新兴策略。虽然RV衰竭是PH的常见临床问题，但目前还没有针对RV的实验治疗方法。PH的主要生理机制之一是内皮功能障碍，导致肺循环一氧化氮(NO)生成减少和NO/cGMP依赖的血管松弛。另外，肺血管cGMP水平也可以通过抑制磷酸二酯酶5(PDE5)来提高，以达到类似的反应。由于PDE5在PH患者的肺和RV中的表达增加，有针对性地增加NO的产生和PDE5的抑制可以抵消导致PH患者心力衰竭心脏后负荷增加的血管收缩。我们已经确定了一个15个氨基酸(FKSRNSRWSCRIKSR)的合成肽(P3)，它能增强内皮细胞一氧化氮合酶(ENOS)的催化活性，并抑制肺动脉内皮细胞和肺动脉平滑肌细胞中cGMP特异性的PDE5。初步数据表明，刺激P3增加了细胞内NO的释放，抑制了cGMP的水解率，并减弱了遥测测得的肺动脉压(PAP)的升高，但不影响体动脉压(SAP)。基于这些初步数据，我们推测P3作为NO释放PDE5抑制剂具有独特的双重作用，为PH的治疗提供了新的治疗途径。为了验证这一假说，本研究的具体目的是：(I)确定P3介导的与eNOS活性增加和NO产生相关的分子事件，特别是钙离子释放，信号模块[磷脂酰肌醇(PI)3-激酶(PI3K)，蛋白激酶B(PKB或Akt)，蛋白激酶A(PKA)和酪氨酸激酶(SrcK)]的激活，小窝蛋白-1(Cav-1)和/或eNOS的磷酸化，以及Cav-1/eNOS的解离，(Ii)阐明P3介导的PDE5/cGMP水解酶的抑制是否与钙释放，PI3K的激活，(Iii)使用与生理相关的低氧诱导的PH动物模型来确定P3的治疗潜力，重点评估P3对进行性和退行性肺血流动力学调节(PAP、SAP、心输出量/心脏指数、红细胞压积和RV肥厚)和与PH相关的血管重构以及毒性的生物利用度、给药方案、疗效和毒性。在临床前动物模型中证实这种新的肽释放PDE5抑制剂功能的基于机制的生理学方法，对于进入治疗PH的I期临床试验是创新的。 公共卫生相关性： 与退伍军人健康的相关性：肺血管疾病和高血压在退伍军人人群中很常见，因为这一人群中与吸烟相关的慢性疾病的发病率很高 阻塞性肺病(COPD)。肺损伤的血管并发症，包括肺高压，也经常在患有成人呼吸窘迫综合征(ARDS)的战斗伤亡受害者中观察到。此外，退伍军人和现役人员暴露在高原、药物、化学品、艾滋病毒感染和血吸虫病等多种危险因素中，可导致肺损伤和进行性肺高压。识别具有NO释放PDE5抑制功能的独特的机制治疗剂为治疗PH提供了一种新的策略。