Ramipril treatment of claudication: oxidative damage and muscle fibrosis

雷米普利治疗跛行：氧化损伤和肌肉纤维化

• 批准号: 9118839
• 负责人: George Pasco Casale
• 金额: $ 93.61万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118839
• 关键词: Activities of Daily Living; Adult; Affect; Age-Years; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Arteries; Atherosclerosis; Biochemistry; Blood; Characteristics; Cilostazol; Clinical; Clinical Trials; Collagen; Comorbidity; Deposition; Deterioration; Event; Exercise Therapy; Exposure to; FDA approved; Fibrosis; Functional disorder; Gait; Gangrene; Gastrocnemius Muscle; Health; Histologic; Histopathology; Homologous Gene; Hypoxia; In Vitro; Intermittent Claudication; Ischemia; Laboratories; Leg; Limb structure; Lower Extremity; Measurement; Mediating; Mediator of activation protein; Mitochondria; Morphology; Muscle; Myalgia; Myopathy; Older Population; PHEMX gene; Pain; Pathway interactions; Patient Care; Patients; Pentoxifylline; Peptides; Performance; Peripheral arterial disease; Pharmaceutical Preparations; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Procollagen; Production; Protocols documentation; Quality of life; Ramipril; Rest; Signal Transduction; Skeletal Muscle; Smooth Muscle Myocytes; Staging; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Transforming Growth Factors; Up-Regulation; Vascular Smooth Muscle; Walking; Work; aggressive therapy; artery occlusion; base; cell growth; claudication; design; disability; experience; improved; mitochondrial dysfunction; novel diagnostics; oxidative damage; randomized trial; targeted agent; targeted treatment; tensin; tissue oxygenation; tool; treatment strategy

 DESCRIPTION (provided by applicant): Patients with claudication experience significant disability and are faced with limited therapeutic options that include only two FDA approved medications Pentoxifylline and Cilostazol which have at best modest effects. A recent clinical trial identified Ramipril as a promising therapeutic agent that produced improvements in walking distances several times those of Pentoxifylline and Cilostazol and similar to those produced by supervised exercise therapy and operative revascularization. The mechanism(s) by which Ramipril produced these effects is unknown. On the basis of our work on the histopathology of lower leg muscle of claudicating patients with peripheral artery disease (PAD) and its relationship to leg function, we have designed the present study aimed at determining how Ramipril produces its beneficial effects in claudicating patients. Our HYPOTHESIS is that Treatment of claudicating PAD patients with Ramipril improves walking performance and quality of life by improving the myopathy of the gastrocnemius. Improved myopathy is a consequence of reduced oxidative damage, reduced TGF-ß1 production by vascular smooth muscle cells and reduced collagen deposition in the affected gastrocnemius. We will test our hypothesis by implementing the following Specific Aims. SPECIFIC AIM #1 will Test the hypothesis that Ramipril-mediated improvements of walking parameters among patients with PAD correlate with improvements in both the morphometrics and biochemistry of myofibers in the gastrocnemius of the impaired limb. SPECIFIC AIM #2 will Test the hypothesis that Ramipril-mediated improvements of walking parameters in patients with PAD, correlate with reduced fibrotic events in small vessels and microvasculature, in association with reduced generalized collagen deposition and improved tissue oxygenation, in the gastrocnemius of the impaired limb. We view vascular smooth muscle cells as the principle mediators of fibrosis in PAD muscle. In SPECIFIC AIM #3 we will use adult human arterial smooth muscle cells (AHASMC), in vitro, to test the hypothesis that the ACE inhibitor Ramipril, which acts as an antagonist of Angiotensin II type 1 receptor (ART1) stimulation by reducing tissue Angiotensin II (Ang II), impedes a mechanism in which Ang II stimulation of ART1 and exposure to hypoxia enhance proliferation of AHASMC and their production of TGF-ß1 and collagen, via stimulation of phosphoinositide-3-kinase signaling and suppression of phosphatase and tensin homologue, a master regulator of cell growth. If our hypothesis is correct, then the work in Aims #1 and #2 will demonstrate for the first time that therapy with Ramipril improves limb function and quality of life by improving the myopathy of skeletal muscles in the ischemic lower limbs. The work in Aim #3 will identify pathways by which hypoxia and Ang II collaborate to induce myopathy in ischemic muscle. Specific agents targeting these pathways could become new treatments for claudication and for more advanced stages of PAD. Finally, information from this study may identify new tools for precise staging of PAD, evaluating therapeutic interventions and identifying patients who will benefit from aggressive therapy.

 描述(由申请人提供)：跛行的患者有严重的残疾，面临的治疗选择有限，只有两种FDA批准的药物己酮可可碱和西洛他唑，充其量只有适度的效果。最近的一项临床试验证实，雷米普利是一种有希望的治疗剂，其步行距离的改善程度是己酮可可碱和西洛他唑的几倍，与监督运动疗法和手术血管重建术产生的效果相似。雷米普利产生这些效应的机制(S)尚不清楚。在我们对外周动脉疾病(PAD)跛行患者小腿肌肉的组织病理学及其与腿部功能关系的研究工作的基础上，我们设计了本研究，旨在确定雷米普利是如何对跛行患者产生有益效果的。我们的假设是，雷米普利治疗跛脚症患者可以通过改善腓肠肌的肌病来改善步行能力和生活质量。肌病的改善是由于氧化损伤减少，血管平滑肌细胞产生的转化生长因子-1减少，以及受影响的腓肠肌中胶原沉积减少。我们将通过实现以下具体目标来验证我们的假设。特殊目的#1将验证这样一个假设，即雷米普利介导的PAD患者步行参数的改善与受损肢体腓肠肌的形态计量学和生化改善有关。特殊目的#2将检验这样一个假设，即雷米普利介导的PAD患者步行参数的改善与受损肢体的腓肠肌中小血管和微血管中纤维化事件的减少、全身胶原沉积的减少和组织氧合的改善相关。我们认为血管平滑肌细胞是PAD肌纤维化的主要介质。在特定的AIM#3中，我们将使用体外培养的成人动脉平滑肌细胞(AHASMC)来测试这一假设，即ACE抑制剂雷米普利通过减少组织血管紧张素II(Ang II)作为血管紧张素II 1型受体(Art1)刺激的拮抗剂，通过刺激磷脂酰肌醇-3-激酶信号和抑制细胞生长的主要调节因子磷酸酶和张力蛋白同源物，阻止Ang II刺激Art1和低氧暴露促进AHASMC增殖及其转化生长因子-β1和胶原的产生的机制。如果我们的假设是正确的，那么目标#1和#2中的工作将证明 雷米普利治疗首次通过改善缺血肢体的骨骼肌病来改善肢体功能和生活质量。AIM#3的工作将确定缺氧和血管紧张素II合作诱导缺血肌肉肌病的途径。针对这些通路的特定药物可能成为治疗跛行和更晚期PAD的新方法。最后，这项研究的信息可能会为PAD的精确分期、评估治疗干预措施和确定将从积极治疗中受益的患者确定新的工具。