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）：跛行患者会经历严重的残疾，并且面临有限的治疗选择，其中仅包括两种 FDA 批准的药物己酮可可碱和西洛他唑，最近的一项临床试验确定雷米普利是一种有前途的治疗药物。步行距离的改善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运重建所产生的效果相似。雷米普利产生的这些作用尚不清楚，根据我们对跛行外周动脉疾病（PAD）患者小腿肌肉的组织病理学及其与腿部功能的关系的研究，我们设计了本研究，旨在确定雷米普利如何产生其作用。我们的假设是，用雷米普利治疗跛行 PAD 患者可以通过改善腓肠肌肌病来改善行走能力和生活质量。肌病是氧化损伤减少、血管平滑肌细胞产生的 TGF-β1 减少以及受影响的腓肠肌中胶原蛋白沉积减少的结果。我们将通过实施以下具体目标 #1 来检验雷米普利的假设。 PAD 患者步行参数的改善与受损肢体腓肠肌肌纤维形态测量和生物化学的改善相关。具体目标#2 将检验以下假设：雷米普利介导的 PAD 患者步行参数的改善与小血管和微脉管系统纤维化事件的减少相关，与受损腓肠肌中全身胶原沉积的减少和组织氧合的改善相关我们将血管平滑肌细胞视为 PAD 肌肉纤维化的主要介质。在具体目标#3 中，我们将使用成人动脉平滑肌细胞。 (AHASMC)，在体外，测试以下假设：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，阻碍 Ang II 刺激的机制ART1 的表达和暴露于缺氧环境中，通过刺激磷酸肌醇 3 激酶信号传导和抑制磷酸酶和张力蛋白同源物，细胞生长的主要调节剂如果我们的假设是正确的，那么目标#1和目标#2中的工作将证明这一点。 雷米普利治疗首次通过改善缺血性下肢骨骼肌肌病来改善肢体功能和生活质量。目标#3的工作将确定缺氧和血管紧张素II共同诱发缺血性肌病的途径。最后，这项研究的信息可能会确定用于精确分期 PAD、评估治疗干预措施和识别将从积极治疗中受益的患者的新工具。治疗。