Peptide Therapy for Pulmonary Arterial Hypertension

肺动脉高压的肽疗法

• 批准号: 8262632
• 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/8262632
• 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）是一种病因多样的破坏性疾病，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、血管重塑、右心室 (RV) 衰竭和心输出量低。尽管其临床影响深远，但过去 25 年的治疗进展已略微改善了 PH 患者的生存率。联合使用现有药物以最大化临床效益是治疗 PH 的新兴策略。尽管 RV 失败是 PH 的常见临床问题，但目前尚无针对 RV 的实验性疗法。 PH 的主要生理机制之一表明内皮功能障碍导致肺循环中一氧化氮 (NO) 产生减少和 NO/环鸟苷 5' 单磷酸 (cGMP) 依赖性血管舒张。或者，也可以通过抑制 5 型磷酸二酯酶 (PDE5) 来升高肺血管 cGMP 水平，以达到类似的反应。由于 PDE5 表达已被证明在 PH 患者的肺部和右心室中增加，因此有针对性地增加 NO 产生和抑制 PDE5 可以抵消血管收缩，从而导致 PH 患者衰竭心脏后负荷增加。我们已经鉴定出一种 15 个氨基酸 (FKSRNSRWSCRIKSR) 合成肽 (P3)，它可以增强肺动脉内皮细胞和肺动脉平滑肌细胞中内皮 NO 合酶 (eNOS) 的催化活性并抑制 cGMP 特异性 PDE5。初步数据表明，P3 刺激可增加细胞内 NO 释放，抑制 cGMP 水解速率，并减弱肺动脉压 (PAP) 的增加，但不会减弱遥测植入的缺氧诱导 PH 清醒大鼠模型中监测到的全身动脉压 (SAP)。基于这些初步数据，我们假设 P3 治疗具有作为 NO 释放 PDE5 抑制剂的独特双重作用，为 PH 的治疗提供了新的治疗方法。为了检验这一假设，本研究的具体目的是：(I) 识别与 eNOS 活性和 NO 产生增加相关的 P3 介导的分子事件，特别关注 Ca2+ 释放、信号模块激活 [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 Src 酪氨酸 (SrcK)]、caveolin-1 (Cav-1) 和/或 eNOS 磷酸化以及 Cav-1/eNOS 解离，(II) 阐明 P3 介导的 PDE5/cGMP 水解抑制是否与 Ca2+ 释放、PI3K 激活、蛋白激酶 G (PKG)/PKA 信号传导、PDE5 磷酸化和/或 抑制 PDE5 的 cGMP 结合，以及 (III) 使用生理相关的缺氧诱导的 PH 动物模型确定 P3 的治疗潜力，特别关注评估 P3 疗法对进行性和回归性肺血流动力学调节的生物利用度、给药方案、功效和毒性（增加 PAP、SAP、心输出量/心脏指数、 血细胞比容和右心室肥大）以及与 PH 和毒性相关的血管重塑。在临床前动物模型中确认这种新型肽释放 NO 的 PDE5 抑制剂功能的基于机制的生理学方法对于推进治疗 PH 的 I 期临床试验具有创新意义。 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管理局患者群体中很常见，因为该群体中与吸烟相关的慢性病的发病率很高 阻塞性肺疾病（COPD）。肺损伤引起的血管并发症（包括 PH）也经常出现在患有成人呼吸窘迫综合征 (ARDS) 的战斗伤亡人员身上。此外，退伍军人和现役人员暴露于多种危险因素，包括高海拔、药物、化学品、艾滋病毒感染和血吸虫病，可导致肺损伤和进行性肺动脉高压。基于机制的具有 NO 释放 PDE5 抑制功能的独特治疗剂的鉴定为 PH 的治疗提供了新的策略。