Effects of Arginase in Right Ventricular Hypertrophy and Failure

精氨酸酶对右心室肥大和衰竭的影响

• 批准号: 8136672
• 负责人: S. Julie-Ann Julie-Ann Lloyd
• 金额: $ 4.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-16 至 2013-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136672
• 关键词: Cyclic GMP; Data; Development; Enzyme Inhibition; Failure; Fibrosis; Laboratories; Lead; Measurable; Modeling; Muscle Cells; NADP; Nitric Oxide; Nitric Oxide Signaling Pathway; Nitric Oxide Synthase; Organ; Pathology; Pathway interactions; Patients; Physiologic intraventricular pressure; Preparation; Process; Protein Overexpression; Pulmonary Circulation; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Reactive Oxygen Species; Right Ventricular Dysfunction; Right Ventricular Hypertrophy; Role; Signal Transduction; Small Interfering RNA; Time; Transfection; Transgenic Mice; Ventricular; Viral; arginase; improved; inhibitor/antagonist; metalloenzyme; pressure; protein expression; research study; rho GTP-Binding Proteins

DESCRIPTION (provided by applicant): The majority of patients with elevated pulmonary vascular resistance die from right ventricular (RV) failure, yet very little is known about this process. We believe that one potential mechanism of action involves signaling via cyclic guanosine monophosphate (cGMP) and nitric oxide (NO). Manipulation of this pathway to increase the concentration of cGMP or NO may prove beneficial to patients with RV failure. We and others have suggested that the NO/cGMP pathway is limited greatly by the unregulation of arginase in cardiopulmonary disease. Arginase, a metalloenzyme that may inhibit endogenous cGMP/NO signaling by directly competing with nitric oxide synthase, thus promoting RV dysfunction. We hypothesize that, in pulmonary hypertension patients, arginase promotes both the development of RV hypertrophy and the progression to failure due to its interaction with the cGMP/NO signaling pathway. We will therefore use a pulmonary artery banding (PAB) model of pulmonary hypertension to determine the role of arginase in RV hypertrophy and failure (Specific Aim 1). We anticipate that arginase inhibition will lead to measurable changes in NO synthase activity as well as ventricular fibrosis and function. Further experiments will aim to elucidate the mechanism of arginase effects in RV hypertrophy and failure signaling through analysis of downstream targets using transgenic mice small interfering RNA and arginase inhibitors (Specific Aim 2). Likely candidates were identified in previous studies and include nicotinamide adenine dinucleotide phosphate (NADPH), reactive oxygen species and Rho-GTPases.

描述（由申请人提供）：大多数肺血管阻力升高的患者死于右心室（RV）衰竭，但对这一过程知之甚少。我们认为，一个潜在的作用机制涉及通过环磷酸鸟苷（cGMP）和一氧化氮（NO）的信号。操纵这一途径，以增加cGMP或NO的浓度，可能会证明有益于RV衰竭的患者。我们和其他人认为，在心肺疾病中，NO/cGMP通路受到呼吸酶失调的极大限制。精氨酸酶，一种金属酶，可能通过直接与一氧化氮合酶竞争抑制内源性cGMP/NO信号传导，从而促进RV功能障碍。我们假设，在肺动脉高压患者中，由于其与cGMP/NO信号通路的相互作用，腺苷酸酶促进RV肥大的发展和衰竭的进展。因此，我们将使用肺动脉结扎（PAB）模型的肺动脉高压，以确定在RV肥大和衰竭（具体目标1）中的作用。我们预计，抑制心肌酶将导致NO合酶活性以及心室纤维化和功能的可测量的变化。进一步的实验旨在通过使用转基因小鼠小干扰RNA和腺苷酸酶抑制剂分析下游靶点，阐明腺苷酸酶在RV肥大和衰竭信号传导中的作用机制（具体目标2）。在先前的研究中确定了可能的候选者，包括烟酰胺腺嘌呤二核苷酸磷酸（NADPH）、活性氧和Rho-GTP酶。